Site of Action of Antibiotics Cell Wall Synthesis

Site of Action of Antibiotics

Cell Wall Synthesis Inhibitors q. Some antimicrobial drugs selectively interfere with synthesis of the bacterial cell wall—a structure that mammalian cells do not possess. q. The cell wall is composed of a polymer called peptidoglycan that consists of glycan units joined to each other by peptide cross-links.

• To be maximally effective, inhibitors of cell wall synthesis require actively proliferating microorganisms. • They have little or no effect on bacteria that are not growing and dividing. • The most important members of this group of drugs are the β-lactam antibiotics (named after the βlactam ring that is essential to their activity).

β-Lactam Antibiotics

Penicillins Ø Most widely effective and the least toxic drugs but increased resistance has limited their use. q. Family differ from one another in: ü the R substituent attached to the 6 - aminopenicillanic acid residue, The nature of this side chain affects: ü Antimicrobial spectrum. ü Stability to stomach acid. ü Crosshypersensitivity. ü Susceptibility to bacterial degradative enzymes (βlactamases)

Mechanism of Action • The penicillins interfere with the last step of bacterial cell wall synthesis (transpeptidation or cross-linkage) • Resulting in exposure of the osmotically less stable membrane. ü Cell lysis can then occur Ø through osmotic pressure Ø through the activation of autolysins. • Bactericidal • Penicillins are only effective against rapidly growing organisms that synthesize a peptidoglycan cell wall. • Inactive against organisms devoid of this structure, such as mycobacteria, protozoa, fungi, and viruses.

Mechanism of Action q Inactivation of Penicillin-binding proteins: Ø bacterial enzymes involved in the synthesis of the cell wall and in the maintenance of the morphologic features of the bacterium. Ø proteins on the bacterial cell membrane.

q. Inhibition of transpeptidase: üPenicillins inhibit this transpeptidasecatalyzed reaction. ü cell wall integrity.

q Inhibition of transpeptidase:

q Production of autolysins: ØDegradative enzymes that participate in the normal remodeling of the bacterial cell wall. Ø In the presence of a penicillin, the degradative action of the autolysins proceeds in the absence of cell wall synthesis. Øpenicillins inhibit: ücell wall synthesis. üdestruction of the existing cell wall by autolysins.

Antibacterial spectrum Ø Penicillins antibacterial spectrum is determined by ü Ability to cross the bacterial peptidoglycan cell wall to reach the PBPs in the periplasmic space. Ø Factors that determine the susceptibility of PBPs to these antibiotics include the size, charge, and hydrophobicity of the particular β-lactam antibiotic. Ø In general, gram-positive microorganisms have cell walls that are easily traversed by penicillins, and absence of resistance they are susceptible to these drugs.

• Gram-negative microorganisms have an outer lipopolysaccharide membrane surrounding the cell wall that presents a barrier to the water-soluble penicillins. • Gram-negative bacteria have proteins inserted in the lipopolysaccharide layer that act as water-filled channels (called porins) to permit transmembrane entrance.

q. Natural penicillins Ø Penicillin G Ø Penicillin V Ø Obtained from fermentations of the fungus Penicillium chrysogenum. q. Semisynthetic penicillins Ø Amoxicillin Ø Ampicillin Ø Attaching different R groups to the 6 -aminopenicillanic acid nucleus. ü Penicillin V is more acid stable than penicillin G. ü Similar spectrum

v. Pencillin inactivation by β-lactamases (penicillinases) that are produced by the resistant bacteria. Ø Despite widespread use and increase in resistance. v. Penicillin remains the drug of choice: ü Gas gangrene (Clostridium perfringens) and ü Syphilis (Treponema pallidum).

q Antistaphylococcal penicillins: Methicillin Nafcillin Oxacillin Dicloxacillin β-lactamase (penicillinase)-resistant penicillins. Their use is restricted to the treatment of infections caused by penicillinase-producing staphylococci, including methicillinsensitive Staphylococcus aureus (MSSA). • Methicillin is not used clinically in the United States except in laboratory tests to identify resistant strains of S. aureus. Because of its toxicity (interstitial nephritis) • MRSA is currently a source of serious community and nosocomial (hospital-acquired) infections and is resistant to most commercially available β-lactam antibiotics. • The penicillinase-resistant penicillins have minimal to no activity against gram-negative infections. • • Ø Ø

Extended-spectrum penicillins • Ampicillin • Amoxicillin • Antibacterial spectrum similar to penicillin G but are more effective against gram negative bacilli. • Widely used in the treatment of respiratory infections • Amoxicillin is employed prophylactically by dentists in high-risk patients for the prevention of bacterial endocarditis. Ø Resistance to these antibiotics is now a major clinical problem because of inactivation by plasmid -mediated penicillinases.

ØFormulation with a β-lactamase inhibitors: • Amoxicillin/ clavulanic acid • Ampicillin/sulbactam üWithout the β-lactamase inhibitor, MSSA is resistant to ampicillin and amoxicillin.

Antipseudomonal penicillins: • Piperacillin • Ticarcillin ü Activity against Pseudomonas aeruginosa • Parenteral formulations only. • Piperacillin is the most potent. • They are effective against many gram-negative bacilli, but not against Klebsiella because of its constitutive penicillinase. Ø Ticarcillin /clavulanic acid Ø Piperacillin /tazobactam ü Extends the antimicrobial spectrum of these antibiotics to include penicillinase-producing organisms.

Resistance qβ-Lactamase activity q. Decreased permeability to the drug q. Altered PBPs

Route of Administration

Depot forms Ø Procaine penicillin G Ø benzathine penicillin G ü IM and serve as depot forms. ü They are slowly absorbed into the circulation and persist at low levels over a long time period.

Pharmacokineics q Absorption: Ø Food decreases the absorption of all the penicillinaseresistant penicillins because as gastric emptying time increases, the drugs are destroyed by stomach acid. Ø Should be taken on an empty stomach. q Distribution: Ø The β-lactam antibiotics distribute well throughout the body. Ø All the penicillins cross the placental barrier Ø No teratogenic effects. Ø Penetration into bone or cerebrospinal fluid (CSF) is insufficient for therapy unless these sites are inflamed. Ø Penicillin levels in the prostate are insufficient to be effective against infections.

q. Metabolism: Host metabolism of the β-lactam antibiotics is usually insignificant. q Excretion: The primary route of excretion is through kidney Ø Patients with impaired renal function must have dosage regimens adjusted. Ø Probenecid inhibits the secretion of penicillins by competing for active tubular secretion via the organic acid transporter increase blood levels. Ø The penicillins are also excreted in breast milk.

Adverse reactions q. Hypersensitivity: ØApproximately 5% percent ØCross-allergic reactions occur among the β-lactam antibiotics. ØPatient history

q. Nephritis: Ø Acute interstitial nephritis ( Methicillin ) q. Neurotoxicity: Ø Seizures if injected intrathecally Ø GABAergic inhibition. q. Hematologic toxicities: Ø Decreased coagulation