Lecture 3: Inhibitors of Cell Wall Synthesis I

Inhibitors of Cell Wall Synthesis Mechanism of Action

Loss of cell-wall integrity following treatment is due to bacteria’s own cell wall remodeling enzymes (autolysins ) that cleave peptidoglycan bonds in the normal course of cell growth, while ICWS prevent new peptidoglycan synthesis

Cell death due to osmotic lysis

Protein synthesis inhibitors (chloramphenicol) prevent synthesis and action of autolysins → prevent action of ICWS (antagonists!)

β-lactams

Penicillins

Cephalosporins

Monobactams

Carbapenems

Other Inhibitors of Cell Wall Synthesis

Vancomycin

Phosphomycin

Bacitracin

Natural Penicillins

Penicillin G

Benzathine penicillin

Procaine penicillin G

Penicillin V

Penicillinase Resistant

Nafcillin

Dicloxacillin

Oxacillin

Methicillin

Extended Spectrum

Ampicillin

Amoxicillin

Antipseudomonal

Piperacillin

Penicillins Mechanism of Action

Penicillin binding proteins (PBPs) are the target of all beta-lactam antibiotics

→ Transpeptidation and transglycosylation are inhibited → cell lysis

Penicillinase

Penicillinase (produced by the bacterium, also called beta lactamase) binds the beta-lactam ring and hydrolyzes the ring, inactivating the antibiotic

Natural Penicillins

highest antibacterial activity against G+ bacteria

some G- coverage, some anaerobic coverage

inactivated by penicillinase

Acidic compound; eliminated by active transport in the kidney

Widely distributed, poor CNS penetration (except inflammation)

Penicillin G (IV, IM)

Penicillin V (oral)

Benzathine penicillin (IM depot)

Procaine penicillin G (IM)

Benzathine penicillin

IM

Longest acting

DOC for syphilis (T. pallidum); prophylaxis

Penicillinase-Resistant Penicillins

lower activity against G+ bacteria

some G- coverage, some anaerobic coverage

resistant to penicillinase

DOC - penicillinase producing S. aureus (G+, MSSA)

Hepatic metabolism and renal excretion

Nafcillin - IM/IV

Dicloxacillin - oral

Oxacillin - oral

Methicillin – testing only, no human use!

MSSA Mechanism of resistance

Resistance is associated with bacterial production of β-lactamase which hydrolyzes the beta-lactam ring to inactivate the drug

MRSA Mechanism of resistance

MRSA produces a mutant form of PBP which decreases the affinity of β-lactams to PBPs (drug can’t bind the target)

NO β-lactam can be used to treat MRSA (except ceftaroline)

Extended Spectrum Penicillins

Lower G+ coverage

extended G- coverage (E. coli, Salmonella, Shigella, H. influenzae, Proteus)

good anaerobic coverage

urinary excretion

inactivated by penicillinase

DOC for Lysteria infections

Ampicillin- oral

Amoxicillin- oral

Ampicillin rash

ampicillin or amoxicillin

generalized dull red, maculopapular rash, generally appearing 3-14 days after the start of therapy

high percentage of patients with infectious mononucleosis (EBV) develop rash

not a hypersensitivity reaction

Antipseudomonal Penicillin

bacteria covered by the extended spectrum penicillins plus some additional enteric Gram negative bacilli (Proteus, Enterobacter, Providencia and Serratia)

major use: Pseudomonas aeruginosa and Acinetobacter

susceptible to penicillinase

renal excretion

Piperacillin – IV/IM

DOC- Pseudomonas aeruginosa w/ concurrent use of aminoglycoside

β-lactamase inhibitors

Addition of β-lactamase inhibitors (clavulanic acid, sulbactam, tazobactam) to ampicillin, amoxicillin, ticarcillin or piperacillin extends the spectrum of these beta-lactam drugs to include many organisms that are resistant by virtue of beta-lactamase production

Penicillin Excretion

Penicillin G is probably the most rapidly excreted drug by normal kidney

Some by glomerular filtration and most by tubular secretion

Tubular secretion can be partially blocked by probenecid

Penicillin crosses placenta, but at a slow rate