MINIREVIEW

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Metallo-␤-Lactamases: Structure, Function, Epidemiology,

Treatment Options, and the Development Pipeline
Sara E. Boyd,a,d David M. Livermore,b David C. Hooper,c William W. Hopea

a Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom

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b Norwich Medical School, University of East Anglia, Norwich, United Kingdom
c
Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
d National Institute for Health Research Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance, Imperial College London,
London, United Kingdom

ABSTRACT Modern medicine is threatened by the global rise of antibiotic resis-

tance, especially among Gram-negative bacteria. Metallo-␤-lactamase (MBL) en-
zymes are a particular concern and are increasingly disseminated worldwide,
though particularly in Asia. Many MBL producers have multiple further drug re-
sistances, leaving few obvious treatment options. Nonetheless, and more encour-
agingly, MBLs may be less effective agents of carbapenem resistance in vivo, un-
der zinc limitation, than in vitro. Owing to their unique structure and function
and their diversity, MBLs pose a particular challenge for drug development. They
evade all recently licensed ␤-lactam–␤-lactamase inhibitor combinations, al-
though several stable agents and inhibitor combinations are at various stages in
the development pipeline. These potential therapies, along with the epidemiol-
ogy of producers and current treatment options, are the focus of this review.

KEYWORDS metallo-␤-lactamase, treatment, pharmacology, drug development,

metalloenzymes

A ntimicrobial therapy is threatened by the global rise of resistance, especially in

Gram-negative bacteria (1), where resistance to ␤-lactams is largely mediated by
␤-lactamases (2). Carbapenems evade most ␤-lactamases but are hydrolyzed by
metallo-␤-lactamases (MBLs) as well as by a few active-site serine ␤-lactamases (SBLs),
notably members of the KPC and OXA-48-like groups. MBLs are chromosomal and
ubiquitous in some nonfermenters, including Stenotrophomonas maltophilia, Aeromo-
nas spp., and Chryseobacterium spp., which are of modest clinical concern. A minority
of Bacteroides fragilis strains have a chromosomally encoded MBL, CfiA or CcrA, but
this is uncommon and is expressed strongly only if an upstream insertion sequence
provides an efficient promoter (3). More important are the acquired MBLs that are
spreading among members of the Enterobacterales and Pseudomonas aeruginosa (4);
these are associated with extremely drug-resistant (XDR) phenotypes, with the produc- Citation Boyd SE, Livermore DM, Hooper DC,
Hope WW. 2020. Metallo-β-lactamases:
ers generally also being resistant to multiple aminoglycosides, fluoroquinolones, and
structure, function, epidemiology, treatment
other agents as well as to ␤-lactams. options, and the development pipeline.
Antimicrob Agents Chemother 64:e00397-20.
https://doi.org/10.1128/AAC.00397-20.
CLASSIFICATION AND DIVERSITY OF METALLO-␤-LACTAMASES
Copyright © 2020 American Society for
␤-Lactamases are classified by two major systems. The first is based on substrate Microbiology. All Rights Reserved.
profiles and vulnerability to inhibitors (5) and places MBLs in its group 3, whereas Address correspondence to Sara E. Boyd,
groups 1 and 2 comprise SBLs. The second classifies ␤-lactamases according to their [email protected].
Accepted manuscript posted online 20 July
amino acid sequences, recognizing four enzyme classes (6). MBLs form class B, while
2020
SBLs are divided among classes A, C, and D (7). The MBLs are structurally and Published 21 September 2020
mechanistically dissimilar from SBLs, suggesting a separate evolutionary origin.

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TABLE 1 Examples of chromosomal and plasmid-associated MBLs (11)

MBL type Species Enzyme(s) Subclass
Chromosomal Bacillus cereus BcII B1
Chryseobacterium indologenes IND B1
Elizabethkingia meningoseptica BlaB B1
Myroides odoratimimus MUS and MYO B1
Bacteroides fragilisa CfiA/CcrA B1
Aeromonas spp. CphA B2
Stenotrophomonas maltophilia L1 B3
Elizabethkingia meningoseptica GOB B3

Plasmid associated Verona integron-encoded metallo-␤-lactamase (VIM) B1

New Delhi metallo-␤-lactamase (NDM) B1
Imipenemase (IMP) B1
Sao Paulo metallo-␤-lactamase (SPM) B1

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German imipenemase (GIM) B1
KHM B1
Dutch imipenemase (DIM) B1
Serratia metallo-␤-lactamase (SMB) B3
Adelaide imipenemase (AIM) B3
aUnlike most other chromosomal MBLs, the Bacteroides fragilis enzyme is rare in the species.

Class B enzymes are further divided into three subclasses—B1, B2, and B3— based
on differences in amino acid sequence at the active site, zinc ligands, zinc stoichiom-
etry, loop architecture, and substrate profiles (8). The important acquired MBLs, com-
prising the IMP, NDM, and VIM types, fall into subclass B1. They hydrolyze all currently
available ␤-lactam antibiotics except monobactams (e.g., aztreonam) (9), as do most or
all other subclass B1 or B3 enzymes. In contrast, the CphA (subclass B2) MBLs of
Aeromonas spp. have narrow-spectrum activity directed exclusively against carbapen-
ems. Irrespective of subclass, MBLs are not inhibited by clavulanic acid, sulbactam,
tazobactam, or avibactam or by developmental penicillanic acid sulfones and diazabi-
cyclooctanes.
The important acquired subgroup B1 MBLs (Table 1) are mostly named based on
where they were first described; thus, for example, Verona integron-encoded metallo-
␤-lactamase (VIM) and New Delhi metallo-␤-lactamase (NDM). The first acquired MBL
(imipenemase; IMP-1), was reported from clinical isolates of P. aeruginosa and Serratia
marcescens in Japan in the 1990s (10), and its family now includes over 85 sequence
variants (11). The first VIM enzyme was found in P. aeruginosa in 1997 (12), with over
69 variants since described (11). NDM—now the most prevalent MBL in Enterobacterales
and Acinetobacter baumannii—was first identified in 2008 in Klebsiella pneumoniae and
Escherichia coli isolates from a patient who had travelled to Sweden from New Delhi,
India (13). Twenty-nine NDM variants have since been described, (11).
It is easy to be dismissive of the chromosomal subclass B2 and B3 MBLs, but recent
reports highlight Stenotrophomonas maltophilia as a multidrug-resistant pathogen in
immunocompromised hosts (14). S. maltophilia carries a subclass B3 MBL (L1 enzyme),
which is unique among MBLs in having four identical subunits (15), in addition to a
chromosomally mediated SBL (L2 enzyme). This combination confers resistance to
almost all ␤-lactams, although MICs vary with methodology, because media affect the
expression and/or function of these enzymes (16). Elizabethkingia meningoseptica has
two chromosomal MBLs, a B1 enzyme (BlaB) and a B3 type (GOB), with the former
predominantly contributing to resistance (17).

GENETIC SUPPORT OF ACQUIRED MBLS

Acquired IMP and VIM enzymes generally are encoded by gene cassettes within
class 1 or class 3 integrons. These may be embedded within transposons, allowing
insertion into the bacterial chromosome or plasmids (18). In contrast, the blaNDM gene
is not integron associated and has been observed on narrow-host-range plasmids
belonging to incompatibility group IncF, in addition to wide-host-range plasmids
belonging to IncA/C, IncL/M, IncH, and IncN (19–22). K. pneumoniae and E. coli are the

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FIG 1 Amino acid residues that bind zinc at the active sites of B1, B2, and B3 MBLs. (A) Crystal structures
of B1 enzymes, including IMP, VIM, NDM, and B. fragilis CcrA, reveal two zinc-binding sites (Zn1 and Zn2).

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The Zn1 site contains three histidine residues (His116, His118, and His196), whereas the ligands for the
Zn2 site are aspartic acid (Asp120), cysteine (Cys221), and histidine (His263). (B and C) There is only one
zinc ion in the active site of the Aeromonas hydrophila enzyme (subclass B2) (B) and two in the active site
S. maltophilia enzyme (subclass B3) (C). (Republished with permission from reference 8.)

frequent hosts of these plasmids, and there are particular associations with K. pneu-
moniae sequence type 11 (ST11), ST14, ST15, and ST147 and E. coli ST167, ST410, or
ST617 (23). These should not, however, be seen as global epidemic strains along the
lines of K. pneumoniae ST258 variants with KPC carbapenemases, for many are common
STs without carbapenemases. In A. baumannii, the blaNDM-1 gene is generally located
within the composite transposon Tn125 and embedded between two copies of a strong
promoter gene ISAba125 (24, 25); it is much less prevalent in this genus than are OXA
carbapenemases (class D).
B2 and B3 MBLs are generally chromosomally encoded, ubiquitous in their host
species, and not transmissible. However, exceptions exist, with horizontal transfer
having been observed. Thus, the AIM-1 MBL (B3) was initially reported, in 2012, to be
encoded by a gene inserted in (and atypical of) the chromosome of a P. aeruginosa
isolate; subsequently, in 2019, it was reported from K. pneumoniae (26). The blaLMB-1
gene, encoding another subclass B3 enzyme, was reported to be located on a plasmid
in Rheinheimera pacifica, where it was flanked by ISCR mobilization sequences, implying
transfer from some other (unknown) source organism. (27). Mobilization of blaSMB-1,
encoding a third subclass B3 enzyme, has occurred similarly (28).

STRUCTURE AND CATALYTIC FUNCTION OF MBLS

Irrespective of subgroup, MBLs contain the ␣␤/␤␣ fold typical of the metallo-
hydrolase/oxidoreductase superfamily (29). The S. maltophilia enzyme has four identical
subunits (15), whereas other MBLs are monomeric.
B1 and B3 MBLs have a shallow active-site groove containing 1 or 2 catalytically
functional divalent zinc ions, flanked by flexible loops (29). In contrast, the B2 enzymes
have an active site that is less accessible and flanked by a helix (30). Except for these
consistencies, MBLs are highly divergent even within subclasses and have as little as
20% sequence identity between subclasses (7). Figure 1 illustrates the amino acid
residues that bind zinc at the active sites of B1, B2, and B3 MBLs (8).
Mechanistically, the zinc ion(s) activates a water molecule, which acts to open the
␤-lactam ring (31). There is no covalent intermediate, as with SBL-mediated catalysis.
Anionic intermediates have been characterized when MBLs hydrolyze carbapenems
(32), but not when NDM-1 enzymes hydrolyze penicillins or cephalosporins (33). In
general, imipenem and meropenem are similarly good substrates for MBLs: for exam-
ple, NDM-1 displays similar catalytic activity, reflected in values of the kcat/Km ratio, for
imipenem (0.09 ␮M⫺1 s⫺1) and meropenem (0.06 ␮M⫺1 s⫺1) (34); biapenem is a
weaker substrate, owing to high Km values, but seems unsuitable for high-dose
development (35).
Differences in assay methodology between workers make it difficult to compare
hydrolytic efficiencies for different MBLs. Variation within, e.g., the VIM, IMP, Sao Paulo

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metallo-␤-lactamase (SPM), and German imipenemase (GIM) family appears largely

inconsequential (36). Nevertheless, subtle but important evolution may be ongoing, as
illustrated in the NDM family. Here, experimental data do not define major differences
in the catalytic efficiencies among NDM-1, -3, -4, -5, -6, -7, and -8 enzymes (37) under
standard conditions, but differences are seen under zinc deprivation. Thus, studies
comparing NDM-1, NDM-4 (Met154Leu), and NDM-12 (Met154Leu, Gly222Asp) dem-
onstrate that the Met154Leu substitution, present in 50% of clinical NDM variants in
some locales, enhances the ability to confer resistance at low Zn2⫹ concentrations (38,
39). This is potentially important because, as discussed below, zinc is restricted in
infection (40) and its scarcity may impede the ability of classical NDM-1 enzyme to
confer clinical resistance. NDM variants that have increased affinity for zinc (up to
⬃10-fold-decreased dissociation constant for zinc [Kd, Zn2]) display selective advantages
in experiments that mimic zinc scarcity imposed by the host immune system (41).

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Perhaps driven by similar pressures, the NDM-15 variant has evolved to function
efficiently as a mono- rather than a bi-zinc enzyme (41). In addition, there are sugges-
tions that NDM enzymes are evolving to develop greater thermodynamic stability (37).

EPIDEMIOLOGY AND DISTRIBUTION OF ACQUIRED MBLs

Bacteria with IMP, VIM, and NDM enzymes have been identified in a range of
community, hospital, and environmental settings (42). Their prevalence and their
importance relative to serine carbapenemases vary greatly by country. Figure 2 illus-
trates the global distribution of acquired MBLs.
Indian subcontinent, Asia, and Russia. The greatest burden of acquired, plasmid-
mediated MBLs lies in South and Southeast Asia (43), where NDM types are prevalent.
As already noted, blaNDM-1 was first identified in bacteria isolated in 2008 from a patient
who had travelled to Sweden from India (44). NDM variants have subsequently been
spread worldwide via patient transfers and travel (45). Epidemiological surveillance has
confirmed that NDM-1 and its variants are widely disseminated throughout India,
Pakistan, and Bangladesh (46, 47); moreover, a review of 39 carbapenem-resistant
Enterobacterales (CRE) collected in India in 2006-2007 by the SENTRY Antimicrobial
Surveillance Program found that 15 harbored blaNDM-1 (48), indicating that it was
circulating prior to its “discovery” in 2008. Enterobacterales with blaNDM were isolated
from public tap water in India (49) and in river systems around pilgrimage sites (42),
demonstrating that the gene has become established beyond health care environ-
ments.
In India, there is frequent cocarriage with other carbapenemases in Enterobacterales
(50); thus, in 2012, of 113 nonclonal CRE isolates at a Mumbai hospital, 106 produced
NDM enzymes, and 21 of these also had a second carbapenemase, most often an
OXA-48-like (n ⫽ 17) or VIM-type (n ⫽ 4) enzyme. Surprisingly, given that most inter-
national reports of NDM enzymes relate to Enterobacterales, P. aeruginosa was the most
common MBL host (24%) among 3,414 carbapenem-resistant Gram-negative bacteria
collected from community and hospital settings in North India (51), with blaNDM-1 (36%)
being the most prevalent carbapenemase gene, followed by blaVIM (18.4%).
Although KPC is the principal carbapenemase among Enterobacterales (CPE) in
China, a survey across 25 provinces showed that 32% of phenotypic carbapenem
resistance in Enterobacterales was linked to blaNDM-1 (52), while a study (2012 to 2016)
of clinical Enterobacter cloacae across three tertiary hospitals found blaNDM-1 to be the
most common carbapenemase gene (80%), followed by blaIMP-26 (8%) and blaIMP-4 (6%)
(53). The importance of IMP MBLs, particularly IMP-4, in China has been underscored by
others; thus, multiple Enterobacterales species carrying a plasmid encoding IMP-4
enzyme were identified from patients with epidemiological links to China (54), and
surveillance at a Beijing hospital highlighted both IMP-4 and NDM-1 in K. pneumoniae
(55). Colocalization of blaNDM-9 and the plasmid-mediated colistin resistance gene mcr-1
was seen in an E. coli strain recovered from retail chicken meat in Guangzhou, China
(56). Having been recognized 30 years ago in Japan, IMP-type enzymes are now
endemic there, though not highly prevalent (57).

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FIG 2 Global distribution of acquired MBLs.

NDM MBLs are the second most prevalent carbapenemases after OXA-48 in the
Middle East, excepting Israel (58, 59). This probably reflects extensive interactions with
the Indian subcontinent. As in India, there is significant penetration of blaNDM into P.
aeruginosa, for which a much greater proportion of carbapenem resistance appears
to be carbapenemase mediated in the Middle East than in Europe or the United
States. Thus, in the Gulf Cooperation Council countries, blaVIM was found in 39% of

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carbapenem-resistant P. aeruginosa isolates (60), with most hosts belonging to inter-

nationally disseminated high risk clones, including ST235, ST111, ST233, ST654, and
ST357 (60). These lineages seem unusually adept at acquiring extrinsic resistance genes.
In Dubai, 32% of resistant P. aeruginosa isolates produced VIM-type MBLs (61), though
a larger proportion had outer membrane impermeability.
The proportion of carbapenem-resistant P. aeruginosa harboring MBLs in Russia rose
from 4.5% between 2002 and 2004 to 28.7% between 2008 and 2010 (62), largely
reflecting the spread of an XDR blaVIM-2-positive ST235 high-risk clone, also present in
Belarus and Kazakhstan (62). NDM is reported as the predominant carbapenemase
among Enterobacterales in St. Petersburg (63, 64), whereas OXA-48 is predominant in
Moscow (65).
Europe. Although Italy had earlier reported both IMP and VIM enzymes (66), Greece

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was the first European country to report extensive dissemination of Enterobacterales
with MBLs. Specifically, K. pneumoniae with VIM carbapenemases were reported from
multiple hospitals in 2003 to 2007, and multilocus sequence typing identified three
major clonal complexes (CCs)—CC147, CC18, and CC14 —among the producers (67). By
2006, 20% of K. pneumoniae isolates collected from hospital wards and 50% of those
from intensive care units (ICUs) monitored by the Greek System for the Surveillance of
Antimicrobial Resistance were carbapenem resistant, largely owing to the spread of the
blaVIM-1 cassette (68). By 2010, KPC had displaced VIM to become the dominant
carbapenemase in Greece, largely through the spread of a K. pneumoniae ST258 variant
(69). Nonetheless, VIM types remained scattered, and they may now be reemerging due
to suppression of the KPC carbapenemases via the use of ceftazidime-avibactam (70).
Elsewhere in Europe, concern about carbapenemases grew following a flurry of
press interest in NDM enzymes from 2008 to 2010 and with the spread of K. pneu-
moniae ST258/512 lineages with KPC carbapenemases in Italy from 2010. The United
Kingdom, taken as an example, recorded a few P. aeruginosa and Enterobacterales
strains with IMP and VIM MBLs before 2008. Thereafter, the number of Enterobacterales
with NDM enzymes increased (46). Most early cases were imports via patients who had
travelled to (and often been hospitalized in) the Indian subcontinent. Multiple NDM
variants have subsequently been reported in the United Kingdom, with NDM-1 being
the most frequent among Enterobacterales, followed by NDM-5 and NDM-7 (71). In
contrast, VIM variants account for 91% of the (uncommon) MBLs in P. aeruginosa, again
associated with international high-risk clones, including ST235, ST111, ST233, and
ST357 (72).
While referral of CPE isolates to the national reference laboratory has increased
100-fold since 2008, many producers are from screening rather than clinical samples.
OXA-48 is now the fastest-spreading carbapenemase, but isolates with NDM enzymes
account for 20 to 25% of CPE submitted. A growing minority of these, particularly E. coli,
have both NDM- and OXA-48-like enzymes (71, 73).
In 2012, the European Centre for Disease Prevention and Control launched its
European Survey of Carbapenemase-Producing Enterobacteriaceae (EuSCAPE) project.
The geographic distribution of enzyme types was estimated by national experts across
38 European countries in 2015 (74). A random sample of carbapenem-susceptible and
-nonsusceptible K. pneumoniae and E. coli strains subsequently were collected prospec-
tively to determine the occurrence of carbapenemases (75). The results, published in
2017, revealed that SBLs (KPC or OXA-48 enzymes) were more prevalent than MBLs in
most countries but that MBLs were widely scattered and were the most prevalent
carbapenemases among Enterobacterales in a few countries. Thus, VIM enzymes were
the dominant carbapenemases in Hungary, and NDM enzymes were dominant in Serbia
and Montenegro. The prevalence of NDM enzymes in the latter countries tallies with
early descriptions of producers linked to these Balkan states. It is unclear whether these
originated as imports from India or as independent local gene escapes from the
unknown source organism (76).

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North America. Infections due to Enterobacterales carrying blaVIM-2, blaVIM-7,

blaIMP-4, and blaIMP-18 genes were recorded in the United States prior to 2005 but, in
general, MBLs remained extremely rare (1, 77). In 2010, Enterobacterales harboring
NDM-1 were isolated from three patients in different states (78) and, as with many
contemporaneous cases in the United Kingdom and elsewhere, the source patients had
all recently been in India or Pakistan (21). Subsequent expansion of NDM enzymes in
the United States has been less marked than in the United Kingdom, with KPC
carbapenemases becoming considerably more prevalent. Nevertheless, until December
2017, 379 CPE with NDM carbapenemases were reported to the CDC from 34 states,
with just under a third (i.e., 109) from Illinois (79), where an outbreak was associated
with contaminated endoscopes.
Enterobacterales with NDM enzymes have been increasing in Canada since 2008, and
these MBLs are now the second most common carbapenemases in the country, with a

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higher prevalence in the western provinces (80). Surveillance conducted between 2007
and 2015 in Toronto revealed that, among 291 clinical CPE, 51% had NDM enzymes,
and 24% of the patients had never received health care abroad or travelled to high-risk
areas (81), suggesting that the enzymes are established locally. In 2019, a novel MBL,
blaCAM-1, was identified from isolates that were collected in 2007 (82). No subsequent
isolates harboring this gene have been reported.
Africa. Because of the paucity of data, the prevalence of CPE carrying MBLs in Africa
is difficult to estimate. Apparent infrequency may reflect true rarity, limited sampling,
or a lack of infrastructure for accurate detection. CPE with VIM MBLs nonetheless have
been identified in Nigeria, Morocco, Algeria, Tunisia, Tanzania, and South Africa, and
CPE with NDM enzymes have been found in Kenya, Nigeria, Morocco, Algeria, Tunisia,
Tanzania, and South Africa (83, 84). Infections caused by Enterobacterales producing
MBLs are reported from both imported and local cases, raising concerns regarding
emerging endemicity (85). Those with IMP-type enzymes have been identified in small
numbers in Morocco, Tunisia, and Tanzania and appear genuinely uncommon (84). An
outbreak caused by Klebsiella spp. carrying blaNDM-5 was reported from a neonatal unit
in Nigeria (86). A concern is that African patients are strongly represented in medical
tourism to India, which is a risk factor for colonization with Enterobacterales producing
MBLs (87).
Rest of the world. KPC enzymes dominate among carbapenemases from Entero-
bacterales in Latin America, with (unusually) some penetration also into P. aeruginosa.
Nonetheless, Enterobacterales with NDM enzymes are endemic in Brazil, with several
outbreaks reported (88). Early case reports of MBL-producing Enterobacterales in Latin
America often concerned members of the Proteeae, including Providencia spp. and
Morganella (89, 90), which are infrequent hosts of blaNDM elsewhere. This creates a
treatment issue, since these genera are inherently resistant to polymyxins and newer
tetracyclines, which remain options against other MBL-producing Enterobacterales
(below).
Unique to South America is the wide distribution in Brazil of P. aeruginosa with
SPM-1 MBL (91), principally associated with an ST277 clone. Outcomes of severe
infections with this clone are often poor, reflecting a lack of good treatment options
(92).
Carbapenemases are rare in Australasia, but there is spread of blaIMP-4 among
Enterobacterales (93), as in parts of China. E. cloacae is a major host, with dissemination
mediated by an IncHI2 plasmid (94). Production of IMP-4 has also been recorded in
Salmonella spp. from domestic pets (95) and seagulls (96), but the significance of this
is uncertain.

MBL FUNCTION IN RESISTANCE, IN VITRO AND IN VIVO

For many years MBLs were perceived as clinically unimportant chromosomally
encoded enzymes from nonpathogenic organisms, notably Bacillus cereus (97, 98). This
perception changed with the recognition that MBLs confer much of the resistance seen
in Chryseobacterium spp. and E. meningoseptica (99) and with heightened awareness of

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the morbidity and mortality associated with S. maltophilia bacteremia (100, 101).
Interest then escalated with the discovery and proliferation of acquired MBLs, especially
NDM-1, which drew extensive press coverage in 2010.
Many MBL producers are broadly resistant in vitro and, on this basis, real concern
exists about lack of treatments. On the other hand, there is evidence that in vivo
resistance to carbapenems may be less than it appears in vitro, because susceptibility
tests are conventionally done in media (e.g., cation-adjusted Mueller-Hinton broth) with
high zinc concentrations (102), whereas the host immune system imposes a state of
zinc deprivation in infection (40, 103). This lack of zinc may not only impede the
catalytic function of MBLs but may also interfere with their protein folding (102) and
may promote degradation of the enzyme in the periplasm (104).
Several preclinical studies suggest a disconnect between high-level in vitro resis-
tance to carbapenems associated with NDM-1 enzymes and a weak ability to protect

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against carbapenems in standard murine infection models (105). Moreover, NDM
enzymes appear to be less effective than other carbapenemases in causing resistance
to carbapenems in patients (106, 107). Thus, mortality in severe infections due to
Enterobacterales with blaNDM appears to be relatively low, ranging from 13% (108) to
55% (109), compared to that seen with bacteria expressing other MBLs (18% to 67%)
(13) or KPC carbapenemases (41% to 65%) (110, 111). Good clinical outcomes have
been reported despite treatment with agents to which NDM enzymes confer resistance
in vitro (106, 107, 112). As yet, there are no studies that confirm or refute whether the
higher-numbered NDM alleles, encoding variants with greater affinity for zinc (above),
are better able to cause clinical resistance than NDM-1 (39, 41).
Finally, it should be underscored that while these indications that NDM MBLs are
less potent in vivo are intriguing, they should be approached with caution. Double-
blinded randomized controlled trials have not been conducted, and existing outcome
data are subject to various biases (113, 114). For VIM MBLs, clinical outcomes correlate
with carbapenem MICs, implying little or no such in vitro-in vivo discordance (115).

CURRENT TREATMENT OPTIONS

Limited data exist to inform clinicians on the optimal treatment for infections caused
by MBL-producing Gram-negative bacteria (106). Cotrimoxazole remains the standard
of care for infections due to S. maltophilia, but most Enterobacterales with acquired
MBLs also have sul and dfr genes, conferring resistance. Genes encoding resistance to
fluoroquinolones and aminoglycosides are often present alongside genes encoding
acquired MBLs. In particular, blaNDM genes are often linked to the genes encoding
ArmA or RmtB methyltransferases, which modify ribosomes to block binding of amin-
oglycosides, including plazomicin; blaIMP and blaVIM generally occur within integrons
that often also carry aac(6=), encoding an acetyltransferase that compromises amikacin
and tobramycin, though not gentamicin or plazomicin (116). A thorough review of
treatment options for MDR and XDR Enterobacterales is available (117). This highlights
observational studies comparing monotherapy to combination therapy for blood-
stream infection (BSI) involving CRE, although few of these were specifically identified
as having MBLs (118, 119).
Colistin. Colistin is the current mainstay of treatment for infections due to MBL
producers. A multinational survey of MBL-producing Enterobacterales and P. aeruginosa
conducted from 2012 to 2014 found ⬎97% susceptibility among MBL-producing P.
aeruginosa strains (variously with IMP, VIM, and NDM enzymes) and ⬎85% for MBL-
producing Enterobacterales (⬎86.1% NDM type and ⬎88.9% IMP type) (83). Exceptions
are Proteeae and Serratia spp., which have intrinsic polymyxin resistance.
For bacteria harboring KPC and OXA-48 carbapenemases, colistin has recently been
shown to be less effective than microbiologically active ␤-lactamase inhibitor combi-
nations (120), making it plausible that an active ␤-lactam likewise would be more
efficacious than colistin against MBL producers. Of note, the emergence of colistin
resistance during treatment, with secondary transmission of resistant variants, is a
concern (121, 122).

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Tigecycline, omadacycline, and eravacycline. The tetracyclines tigecycline, om-

adacycline, and eravacycline have strong in vitro activity against many MBL-producing
Enterobacterales, except Proteeae, although not against P. aeruginosa. During November
2018, 275 unique Enterobacterales isolates carrying blaNDM collected by the U.S. Centers
for Disease Control and Prevention were tested with tigecycline (86.5% susceptible,
based on a ⱕ2-␮g/ml FDA breakpoint), eravacycline (66.2% susceptible, based on a
ⱕ0.5-␮g/ml FDA breakpoint), and omadacycline (59.6% susceptible, based on a ⱕ4-
␮g/ml breakpoint) (123). The higher susceptibility rate for tigecycline than eravacycline
reflects the higher FDA breakpoint for Enterobacterales; in Europe, both agents have an
identical 0.5-␮g/ml breakpoint, and eravacycline is the more active on a simple
gravimetric basis, though it is unclear whether this confers a clinical advantage (124).
Merits of omadacycline are its minimal known drug interactions and its ability to be
administered orally (125); however, it has the least relevant license (for community-

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acquired bacterial pneumonia and acute bacterial skin and skin structure infections) in
relation to the clinical burden of MBL producers.
While the in vitro activity of these tetracyclines is encouraging, there are multiple
caveats. First, tigecycline carries an FDA “black box” warning of increased mortality
when the drug was used as monotherapy (126); second, both tigecycline and erava-
cycline have failed to achieve noninferiority to comparators in one or more clinical trials
(ventilator-associated pneumonia and diabetic foot infection for tigecycline, compli-
cated urinary tract infection [cUTI] for eravacycline); third, there is little provenance for
tetracyclines as monotherapy in the severely ill patients who commonly develop
infections due to MBL-producing opportunists; fourth, particularly for tigecycline, the
disparity between EUCAST (ⱕ0.5 ␮g/ml) and FDA (ⱕ2 ␮g/ml) susceptibility breakpoints
creates categorization uncertainty; last, the lack of anti-Proteeae activity is important in
Latin America, where Providencia spp. are frequent hosts of blaNDM (127). Given these
uncertainties, the best advice is to consider using these tetracyclines in combination
against MBL producers, not as monotherapy.
Aztreonam. Aztreonam is stable to MBLs, though activity is lost against organisms
that coproduce extended-spectrum ␤-lactamases (ESBLs) or AmpC enzymes (128),
which are common in MBL-producing Enterobacterales. Clinical experience with aztreo-
nam as monotherapy is lacking for MBL producers, although some success was
recorded when aztreonam was used in combination with ceftazidime-avibactam (129,
130), with avibactam serving to inhibit ESBLs. Six of 10 patients survived following
treatment with this combination during an outbreak of K. pneumoniae with NDM-1,
OXA-48, and CTX-15 ␤-lactamases in Barcelona (129). Although no adverse events were
reported, the safety is unclear, and it is difficult to match the regimen of aztreonam-
avibactam (1.5 g ⫹ 0.5 g every six hours [q6h]) that is presently being developed (see
below).
Fosfomycin. Fosfomycin commonly retains full in vitro activity against MBL-producing
Enterobacterales and has been successful in trials, very recently, as an i.v. agent in cUTI (131).
It may be an option against MBL producers—particularly E. coli, which is more suscep-
tible than other Enterobacterales— but it is mainly advocated for use in combination
due to concerns about emergence of resistance, particularly in Klebsiella spp. (132).
Fosfomycin has little direct antipseudomonal activity, with typical MICs above break-
points. However, in vitro synergy is seen when fosfomycin is combined with mero-
penem against MBL-producing P. aeruginosa strains (133), suggesting a need for in vivo
exploration.

DEVELOPMENT PIPELINE
The development pipeline represents four main strategies against MBL producers: (i)
protection of MBL-stable-monobactams from other coproduced ␤-lactamases, as, e.g.,
with aztreonam-avibactam; (ii) development of ␤-lactams stable to MBLs as well as
SBLs, as with, e.g., cefiderocol and BOS-228; (iii) combinations of cephalosporins and
carbapenems with triple-action diazabicyclooctanes (DBOs); and (iv) direct inhibition of
MBLs with cyclic boronates, thiols, chelators, dicarboxylic acids, and other agents.

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Aztreonam-avibactam. Aztreonam-avibactam is the first antibiotic to be developed

under a public-private partnership agreement (134, 135), with partial financing from the
European Union’s Innovative Medicine’s Initiative and, latterly, also the U.S. Biomedical
Advanced Research and Developmental Authority (BARDA). A prospective randomized
phase 3 study (NCT03580044) is scheduled to begin in 2020 to determine efficacy,
safety, and tolerability versus best available therapy (BAT) for hospitalized adults with
complicated intra-abdominal infections (cIAI), nosocomial pneumonia (NP), cUTI, or BSI
due to MBL-producing Gram-negative bacteria (135).
Aztreonam evades hydrolysis by MBLs (128) but is compromised by the ESBL and
AmpC enzymes that are coproduced by many MBL-positive CPE. These SBLs are
inhibited by avibactam, a diazabicyclooctane (DBO) (136, 137), and consequently,
MBL-producing Enterobacterales that also carry ESBLs or AmpC are susceptible to

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aztreonam-avibactam in vitro (138) and in vivo (139). The combination is less reliably
active against MBL-producing P. aeruginosa (140), because aztreonam has weak
antipseudomonal activity.
Considerable interest in this approach exists, because the safety and efficacy of
aztreonam are well established and because avibactam was established to be effective
at inactivating ESBLs and AmpC enzymes during trials with ceftazidime. Moreover, case
reports suggest success against infections caused by MBL producers when aztreonam
was coadministered with ceftazidime-avibactam (see “Aztreonam” above) (129, 130).
MBL-stable ␤-lactams. (i) Cefiderocol (S-649266). Cefiderocol (S-649266) is a
novel parenteral siderophore cephalosporin designed by Shionogi & Co., Ltd., with a
catechol linked to its 3-position side chain. It is licensed in the United States for cUTI
and in the European Union and United Kingdom for “treatment of infections due to
aerobic Gram-negative organisms in adults with limited treatment options” (141). It is
retained among developmental agents here, rather than being included in the estab-
lished treatments, because there is little published experience with MBL producers to
date (142, 143).
Critically, the catechol moiety forms a chelation complex with ferric iron, and this
complex is actively accumulated by Gram-negative bacteria, which are forced to
scavenge this essential element (144). Cefiderocol has good activity in vitro under iron
starvation against Gram-negative bacteria, including CPE, P. aeruginosa, and A. bau-
mannii (145). It is relatively stable to both SBLs and MBLs (144); however, the MICs for
Enterobacterales and nonfermenters with NDM carbapenemases tend to be slightly
higher than those for isolates of the same species with other carbapenemase types
(146). Cefiderocol proved effective against carbapenem-resistant P. aeruginosa (ex-
pressing IMP-1 enzymes), A. baumannii (expressing OXA-51-like enzymes), and K.
pneumoniae (expressing NDM-1 enzymes) in immunocompetent rat respiratory tract
infection models, achieving a ⱖ3-log reduction in the number of viable bacteria in the
lungs when given over 4 days so as to recreate the human exposures of an infusion
regimen involving 2 g q8h given i.v. for 3 h (147). Efficacy decreased when the infusion
time was reduced to 1 h, owing to a lower percentage of the dosing interval during
which free-drug concentrations were above the MIC (Tf ⬎MIC) (147). Interestingly, the
mean Tf ⬎MIC required for a 1-log10 reduction was 18 to 24% greater for A. baumannii
isolates (expressing OXA-23 or OXA-24) in the murine lung infection model than for
Enterobacterales expressing NDM-1, NDM-4, or KPC-2 enzymes and for P. aeruginosa
isolates expressing IMP-1 or VIM-10 MBLs (148).
In humans, the infusion regimen of 2 g q8h i.v. over 3 h provided ⬎90% probability
of target attainment (PTA) with 75% Tf ⬎MIC for MICs of ⱕ 4 ␮g/ml for patients with
normal renal function (149). A phase 3 trial (NCT03032380) has shown noninferiority to
meropenem in nosocomial pneumonia (150). Less encouragingly, another trial
(NCT02714595) found excessive deaths in the cefiderocol arm, compared with best
available therapy, for patients with severe infections caused by carbapenem-resistant
Gram-negative pathogens (151). Full analysis is awaited but, notably, deaths were
mostly associated with Acinetobacter infections (152), not Enterobacterales.

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(ii) BOS-228 (formerly LYS228). BOS-228 is a monobactam and, like aztreonam, is

stable to MBLs (153). Unlike aztreonam, it is also stable to many potent SBLs, including
carbapenemases, ESBLs, and AmpC types (154); BOS-228 binds to penicillin-binding
protein 3 (PBP3) similarly to aztreonam, in addition to weak binding to PBP1a and
PBP1b of Enterobacterales (155). BOS-228 had an MIC90 of 2 ␮g/ml for a clinical panel
of 88 Enterobacterales isolates expressing ESBLs, KPCs, and MBLs (153), and no single-
step mutants were selected from 12 ␤-lactamase-expressing Enterobacterales exposed
to the drug at 8⫻ MIC, though mutants were selected from 2/12 strains, neither of
which expressed MBLs, at 4⫻ MIC (155).
A randomized evaluator-blinded multicenter phase 2 trial (NCT03354754) to evalu-
ate pharmacokinetics, clinical responses, safety, and tolerability of BOS-228 in cIAI
commenced in 2018. The drug is being administered as i.v. monotherapy (without

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metronidazole) q6h for at least 5 days and compared to standard of care, with out-
comes evaluated at day 28. A randomized controlled evaluator-blinded multicenter trial
(NCT03377426) in cUTI has also been initiated.
Cephalosporins or carbapenems combined with triple-action DBOs—zidebac-
tam and nacubactam. Unlike with cyclic boronates (see below), it has not been
possible to discover DBOs that directly inhibit MBLs. However, nacubactam and zide-
bactam are DBO analogs that combine inhibition of SBLs with direct antibacterial
activity by inhibiting PBP2 (156). When combined with PBP3-targetted ␤-lactams, this
attack on PBP2 leads to an “enhancer” effect, with further ␤-lactamase inhibition-
independent synergy observed (156, 157). Consequently, cefepime-zidebactam and
cefepime- or meropenem-nacubactam combinations are active in vitro against ⬎75%
of MBL-producing Enterobacterales and, in cefepime-zidebactam’s case, also against
many MBL-producing P. aeruginosa strains (158).
Although the direct antibacterial activity of nacubactam and zidebactam is readily
lost via mutations compensating for inhibition of PBP2 (159), the enhancer effect is
retained, with many of the mutants consequently remaining susceptible to, e.g.,
cefepime-zidebactam or meropenem-nacubactam at low concentrations (156, 157).
Cefepime-zidebactam is currently the most advanced of these combinations, with a
phase 3 trial due to commence (160).
Direct inhibitors of MBLs. (i) Cyclic boronates—VNRX-5133 (taniborbactam)
and QPX7228. Inhibitors that target both SBLs and MBLs are of great interest but have
proved difficult to obtain owing to structural and functional differences between and
among these enzymes. This combination of inhibitory activities nonetheless has re-
cently been achieved with several cyclic boronates, notably taniborbactam and
QPX7228. These mimic the tetrahedral anionic intermediate common to SBL and MBL
catalysis (161) and additionally inhibit some penicillin-binding proteins (e.g., PBP 5,
which is nonessential) by the same mechanism (162). They represent a considerable
expansion in spectrum over vaborbactam, their progenitor, which inhibits only few
class A ␤-lactamases, notably KPC types (163).
Taniborbactam (VenatoRx) is the more advanced of these two boronates and is in
phase III trials combined with cefepime (164). It irreversibly inhibits class A, C, and D
SBLs and is a reversible competitive inhibitor of VIM and NDM MBLs, though not of IMP
types (165). Safety has been established in healthy volunteers (NCT02955459), and the
FDA has allowed cefepime-taniborbactam to proceed via a fast-track pathway for the
clinical indications of cUTI and cIAI. QPX7728 (QPEX) likewise inhibits both SBLs and
MBLs: 50% inhibitory concentrations (IC50) for KPC enzymes are around 2.9 ⫾ 0.4 nM,
compared with 22 ⫾ 8 nM for the class C cephalosporinase of E. cloacae P99,
55 ⫾ 25 nM for the NDM-1 MBL, and 14 ⫾ 4 nM for VIM-1. As with taniborbactam, the
IC50 for IMP-1 is considerably higher, at 610 ⫾ 70 nM (166). An i.v. combination of
QPX7728 with meropenem is being explored. This significantly lowered bacterial
counts in murine thigh and lung infection models with carbapenem-resistant K. pneu-
moniae, P. aeruginosa, and A. baumannii compared to meropenem alone, although
strain genotypes were not reported. Unlike taniborbactam, QPX7228 is orally bioavail-

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able, and combinations with ceftibuten and tebipenem were evaluated in vitro against
CPE, including those with MBLs (167).
(ii) Thiol-containing MBL inhibitors and chelating agents. Small molecules that
bind and/or chelate zinc ions include thiols, dicarboxylates, hydroxamates, and tetra-
zoles; these are widely reported to inhibit MBLs, but human metalloproteases are
vulnerable too, so toxicity may preclude clinical development.
Thiol-containing compounds inhibit all MBL subtypes (B1, B2, and B3) (168), with
strong competitive inhibition of IMP-1 by thioester derivatives first being reported in
1999 (169). The dipeptide L-captopril deserves mention in this context. It is used as an
ACE (angiotensin-converting enzyme) inhibitor in the treatment of hypertension and is
reported also to inhibit MBLs by chelating the active-site zinc ions via its thiol group
(170); the corresponding D-stereoisomer is a more potent inhibitor and can potentiate

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meropenem against strains with VIM-2 MBLs (170). Both captopril isomers act via zinc
chelation, and repurposing is attractive, given the known safety of the L-isomer at its
licensed dose; however, the economic model for development is yet to be established,
and safety issues for the D-isomer need exploration. Other thio-carbonyl compounds,
such as thiomandelic acid, exhibit synergy with meropenem against Enterobacterales
with VIM, NDM, and IMP enzymes (171).
Bisthiazolidines are carboxylate-containing bicyclic compounds, considered penicil-
lin analogs that inhibit MBLs through a zinc-bridging thiol group and a carboxylate that
interacts with K224 (172). The orientations of the carboxylate and thiol moieties create
diverse binding that is observed on X-ray crystal structures and has been shown to
inhibit all MBL types (173). The bisthiazolidine scaffold inhibits NDM-1 enzymes in vitro,
with Ki values in the low micromolar range (from 7 ⫾ 1 to 19 ⫾ 3 ␮M); they restore
imipenem activity against E. coli strains producing NDM-1 (172).
ANT2681 (Antabio) is the lead compound from a series of thiazole carboxylate
derivatives which inhibit NDM and VIM through interaction with the dinuclear zinc ion
cluster present at the active site (189, 190). It binds in a noncovalent competitive
manner with respect to the substrate and is in late-stage preclinical development.
The divalent cation chelator EDTA has raised interest, too, both as an inhibitor of
MBLs and because it disrupts the Gram-negative outer membrane and neutralizes
various bacterial enzymes and toxins (174, 175). It is widely used in identification tests
for MBLs. Sodium calcium EDTA, which is licensed for use for treatment of lead
poisoning, reportedly restored imipenem’s activity in vivo against P. aeruginosa strains
producing IMP and VIM enzymes and against E. coli strains producing NDM-1 enzyme
(176, 177), raising the issue of whether it might be used to potentiate carbapenems in
human infections. Elores, which is marketed in India, combines ceftriaxone, sulbactam,
and EDTA (178, 179) and reportedly achieved cures of infections due to MBL producers
in multiple patients, with no serious adverse events (178). However, prospective and
controlled studies are lacking, the dose of EDTA is low, and there remains uncertainty
(see above) about the function of NDM-1 in vivo. More negatively, the FDA has placed
strict limits on the amount of EDTA permissible even in food (180), and sodium calcium
EDTA is capable of producing toxic effects that can be fatal (181). High concentrations
of EDTA are likely to strip divalent cations from human metalloenzymes, including
matrix metalloproteinases, carbonic anhydrase, and carboxypeptidases, thus limiting
clinical applicability.
Aspergillomarasmine A (AMA) is a fungal natural product discovered in the 1960s
(182) and reevaluated in the 1980s as an inhibitor of the human metalloproteinase
angiotensin-converting enzyme (ACE). AMA inhibits MBLs via a metal ion seques-
tration mechanism and displays rapid and potent inhibition of NDM-1 and VIM-2
enzymes in vitro (183). It restored the activity of meropenem against a K. pneu-
moniae strain expressing NDM-1 enzyme in an intraperitoneal murine infection
model (184). Again, the hazard of inhibiting human metalloenzymes requires
careful investigation.

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CHALLENGES FOR THE DEVELOPMENT OF INHIBITORS OF MBLS

One of the biggest challenges in designing MBL inhibitors is the diversity among
these enzymes, which share less than one-third sequence identity at their active sites.
Thus, for example, taniborbactam and QPX7728 target NDM and VIM enzymes, but not
IMP types (185). Development of inhibitors that bind remotely from the active site
might overcome this limitation, but possible target areas also vary within class B1 and
seem even better able to tolerate mutations than the active site (29). Another challenge
is the shallow binding site in B1 enzymes, meaning that inhibitors can carry out only
limited interactions (29). Specificity for bacterial MBLs is a further recurring challenge;
interactions with human metalloenzymes and contingent toxicity are major concerns.
Molecules that solely inhibit MBLs are limited by the fact that many MBL producers also
coproduce SBLs, including carbapenemases, meaning that the partner ␤-lactam must

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evade these enzymes, that the inhibitor must inactivate both MBLs and SBLs, or that a
second inhibitor is required.
Preclinical development is challenging, too, because it is difficult to establish reliable
animal models in which MBL-mediated resistance is expressed, perhaps owing to the
already-mentioned lack of essential zinc at infection sites. Moreover, bacteria are prone
to lose MBL-encoding plasmids, or fail to reliably express them, in murine models,
resulting in pharmacodynamic data that suggest meropenem susceptibility (186, 187).
Consequently, it is difficult to establish the efficacy of candidate MBL-stable drugs or
inhibitor combinations. It is unclear if the same phenomena occur in patients (188), and
this requires further research. Irrespective of this aspect, it is also challenging to find
and recruit the required number of patients with MBL-producing pathogens to clinical
trials. Rapid diagnostics should help, but their use is complicated by cost and the need
to deploy them to all trial sites, including in countries where they are not licensed or
are licensed only to inform infection control, not treatment.

CONCLUSION
MBLs are disseminating internationally, particularly in Asia, and often are produced
by Gram-negative bacteria with extremely broad spectra of in vitro resistance. Unlike for
KPC and OXA-48-like carbapenemases, producers are typically not susceptible to
recently licensed ␤-lactamase inhibitor combinations such as ceftazidime-avibactam,
meropenem-vaborbactam, imipenem-relebactam, although cefiderocol may be a po-
tential answer. The ability of MBLs to confer resistance to carbapenems may not be as
great in vivo as in vitro, though this is uncertain and may vary by enzyme type even
within MBL subclasses.
Inhibitors are known, and the developmental compounds boronates, taniborbac-
tam, and QPX7728 are of particular interest. Nonetheless, the quest for effective
inhibitors is complicated by differences in active-site structure and zinc ligand interac-
tions among MBLs and by difficulties in the design of appropriate preclinical and
clinical trials. Nonboronate inhibitors face toxicity issues, particularly if they interact
with other metalloenzymes or are general chelators. Other approaches to overcoming
MBLs include avibactam-protected aztreonam; stable ␤-lactams, notably BOS-228 as
well as cefiderocol; and combinations of ␤-lactams with triple-action DBOs, notably
cefepime-zidebactam and meropenem-nacubactam.
And that is the positive aspect on which to close: there is now a diverse and exciting
pipeline of potential agents for the treatment of infections caused by bacteria that
produce MBLs. It remains to be seen which will be the most effective of these agents.

ACKNOWLEDGMENTS
S.E.B. is funded by a UKRI Innovation Fellowship through the North West MRC
Scheme in Clinical Pharmacology and receives research support from Roche Pharma.
D.M.L. serves on advisory boards or has ad-hoc consultancy with Accelerate, Allecra,
Antabio, Centauri, Entasis, GlaxoSmithKline, J&J, Meiji, Melinta, Menarini, Mutabilis,
Nordic, ParaPharm, Pfizer, QPEX, Roche, Sandoz, Shionogi, T.A.Z., Tetraphase, VenatoRx,
Wockhardt, and Zambon; has delivered paid lectures for Astellas, bioMérieux, Beckman

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Minireview Antimicrobial Agents and Chemotherapy

Coulter, Cardiome, Cepheid, Merck/MSD, Menarini, Nordic, Pfizer, and Shionogi; and has
relevant shareholdings or options in Dechra, GSK, Merck, Perkin Elmer, Pfizer, and T.A.Z.,
amounting to ⬍10% of portfolio value. D.C.H. is a consultant for Selux Diagnostics, Day
Zero Diagnostics, Wockhardt Pharmaceuticals, and Shionogi Pharmaceuticals. W.W.H.
holds or has recently held research grants with F2G, Astellas Pharma, Spero Therapeu-
tics, Antabio, Allecra, Bugworks, and NAEJA-RGM; holds awards from the Medical
Research Council, National Institute of Health Research, FDA, and the European Com-
mission; and has received personal fees in his capacity as a consultant for F2G, Amplyx,
Ausperix, Spero Therapeutics, VenatoRx, Pfizer, and BLC/TAZ.

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