Drugs, Microbes, Host – The

Elements of Chemotherapy
Selectively toxic Targets of antimicrobial drugs

• Drugs should kill or inhibit

1. Inhibition of cell wall
microbial cells without
synthesis
simultaneously damaging host
2. Inhibition of nucleic acid
tissues.
synthesis, structure or
• As the characteristics of the function
infectious agent become more 3. Inhibition of protein
similar to the vertebrate host cell, synthesis
complete selective toxicity 4. Disruption of cell membrane
becomes more difficult to achieve structure or function
& more side effects are seen.
 1. Drugs that affect the bacterial
cell wall
• Most bacterial cell walls contain a rigid girdle of
peptidoglycan.
• Penicillin and cephalosporin block synthesis of
peptidoglycan, causing the cell wall to lyse.
• Penicillins do not penetrate the outer membrane
and are less effective against gram-negative
bacteria.
• Broad spectrum penicillins and cephalosporins
can cross the cell walls of gram-negative
bacteria.
 2. Drugs that inhibit nucleic acid
synthesis
• may block synthesis of nucleotides, inhibit
replication, or stop transcription
• Sulfonamides and trimethoprim block
enzymes required for tetrahydrofolate
synthesis needed for DNA & RNA synthesis.
• competitive inhibition – drug competes with
normal substrate for enzyme’s active site
• synergistic effect – an additive effect,
achieved by multiple drugs working together,
requiring a lower dose of each
3. Drugs that block protein synthesis
• Ribosomes of eucaryotes differ in size and
structure from procaryotes, so antimicrobics
usually have a selective action against
procaryotes. But they can also damage the
eucaryotic mitochondria.
• Aminoglycosides (streptomycin, gentamicin)
insert on sites on the 30S subunit and cause
misreading of mRNA.
• Tetracyclines block attachment of tRNA on
the A acceptor site and stop further
synthesis.
4. Drugs that disrupt cell membrane
function
• A cell with a damaged membrane dies from
disruption in metabolism or lysis.
• These drugs have specificity for a particular
microbial group, based on differences in
types of lipids in their cell membranes.
• Polymyxins interact with phospholipids and
cause leakage, particularly in gram-negative
bacteria
• Amphotericin B and nystatin form
complexes with sterols on fungal
membranes which causes leakage.
Survey of major antimicrobial drug groups Antibacterial antibiotics

• Antibacterial drugs Penicillins

– Antibiotics
Cephalosporins
– Synthetic drugs
• Antifungal drugs
Other beta-lactam
• Antiparasitic drugs antibiotics
• Antiviral drugs Aminoglycosides
About 260 different antimicrobial Tetracycline antibiotics
drugs are classified in 20 drug Chloramphenicol
families.
Other Streptomyces
antibiotics
The Bacillus antibiotics
New classes
 Penicillins
• Large diverse group of compounds
• Could be synthesized in the laboratory
• more economical to obtain natural penicillin
through microbial fermentation and modify it to
semi-synthetic forms
• Penicillium chrysogenum – major source
• All consist of 3 parts
– thiazolidine ring
– beta-lactam ring
– variable side chain dictates microbial activity
 Penicillins
• Penicillins G and V most important natural forms
• Penicillin is the drug of choice for gram-positive
cocci (streptococci) and some gram-negative
bacteria (meningococci and syphilis spirochete)
• Semisynthetic penicillins – ampicillin,
carbenicillin & amoxicillin have broader spectra –
gram negative enterics rods
• Penicillinase-resistant – methicillin, nafcillin,
cloxacillin
• Primary problems – allergies and resistant
strains of bacteria
 Cephalosporins
• Account for majority of all antibiotics
administered
• Isolated from Cephalosporium acremonium mold
• Beta-lactam ring that can be altered
• Relatively broad-spectrum, resistant to most
penicillinases, & cause fewer allergic reactions
• Some are given orally, many must be
administered parenterally
 Cephalosporins
• 3 generations exist
• First generation – cephalothin, cefazolin – most
effective against gram-positive cocci
• Second generation – cefaclor, cefonacid – more
effective against gram-negative bacteria
• Third generation – cephalexin, cefotaxime –
broad-spectrum activity against enteric bacteria
with beta-lactamases
• Ceftriaxone – new semisynthetic broad-spectrum
drug for treating wide variety of infections
 Other beta-lactam antibiotics
• Imipenem – broad-spectrum drug for
infections with aerobic and anaerobic
pathogens
• Azeotreonam –isolated from bacteria
Chromobacterium violaceum – newer
narrow-spectrum drug for infections by
gram-negative aerobic bacilli. May be
used by people allergic to penicillin.
 Aminoglycosides
• composed of 2 or more amino sugars and an
aminocyclitol (6C) ring
• products of various species of soil actinomycetes in
genera Streptomyces & Micromonospora
• Broad-spectrum, inhibit protein synthesis, especially
useful against aerobic gram-negative rods & certain
gram-positive bacteria
– Streptomycin – bubonic plague, tularemia, TB
– Gentamicin – less toxic, used against gram-negative rods
– Newer – Tobramycin & amikacin gram-negative bacteria
Tetracycline antibiotics Chloramphenicol

• Broad-spectrum, block Isolated from Streptomyces

protein synthesis venezuelae
Potent broad-spectrum drug with
• Doxycycline & unique nitrobenzene structure
minocycline – oral Blocks peptide bond formation
No longer derived from natural
drugs taken for STDs, source
Rocky Mountain Very toxic, restricted uses, can
spotted fever, Lyme cause irreversible damage to
bone marrow
disease, typhus, acne Typhoid fever, brain abscesses,
& protozoa rickettsial & chlamydial infections
 Other Streptomyces antibiotics
• Clindamycin – broad-spectrum, serious
abdominal anaerobic infections
• Vancomycin –narrow-spectrum, effective
against penicillin & methicillin resistant
staphylococcal infections; very toxic, hard
to administer
• Rifampin – limited spectrum, cannot pause
through many cell membranes, used to
treat gram-positive bacteria, TB, leprosy
Synthetic antibacterial drugs Miscellaneous antibacterial drugs

Isoniazid –used with rifampicin to treat

TB
• Sulfonamides, sulfa drugs – Oxazolidinones- new class of
first antimicrobic drugs antibacterial drugs inhibit initiation of
• Sulfisoxazole – shigellosis, protein synthesis
UTI, protozoan infections Linezolid – MRSA, VRE
• Silver sulfadiazine –burns, Fluoroquinolones –broad-spectrum,
eye infections potent
• Trimethoprim – given in norfloxacin, ciprofloxacin – UTI,
combination with STD, GI, osteomyletitis,
sulfamethoxazole – UTI, respiratory & soft tissue infections
PCP sparofloxacin, levofloxacin –
pneumonia, bronchitis, sinusitis
 Antifungal drugs
• Macrolide polyene
– Amphotericin B –mimic lipids, most versatile &
effective, topical & systemic treatments
– Nystatin – topical treatment
• Griseofulvin – stubborn cases of dermatophyte
infections, nephrotoxic
• Synthetic azoles – broad-spectrum;
ketoconazole, clotrimazole, miconazole
• Flucytosine – analog of cytosine; cutaneous
mycoses or in combination with amphotericin B
for systemic mycoses
 Antiparasitic drugs
• Antimalarial drugs – quinine, chloroquinine,
primaquine, mefloquine
• Antiprotozoan drugs - Metronidazole (Flagyl),
quinicrine, sulfonamides, tetracyclines
• Antihelminthic drugs – immobilize, disintegrate,
or inhibit metabolism
– mebendazole, thiabendazole- broad-spectrum –
inhibit function of microtubules, interfers with glucose
utilization & disables them
– pyrantel, piperazine- paralyze muscles
– niclosamide – destroys scolex
 Antiviral drugs
• Block penetration into host cell
• Block transcription or translation
– Nucleotide analogs
• Acyclovir – herpesviruses
• Ribavirin- a guanine analog – RSV, hemorrhagic fevers
• AZT – thymine analog - HIV
• Prevent maturation of viral particles
– Protease inhibitors – HIV
• Interferon - HCV
Mechanisms drug resistance Side effects of drugs

• Drug inactivation – 1. Toxicity to organs

penicillinases 2. Allergic responses
• Decreased permeability 3. Suppression and
to drug or increased alteration of microflora
elimination of drug from
cell
• Change in metabolic
patterns
• Change in drug
receptors
• Minimum inhibitory concentration (MIC)-
smallest concentration of drug that visibly
inhibits growth
• Therapeutic index – the ratio of the dose
of the drug that is toxic to humans as
compared to its minimum effective dose