Antibiotics Inhibiting Cell Wall Synthesis


Antibiotics Inhibiting Cell Wall Synthesis

All beta-lactam drugs (penicillins and cephalosporins) are strong and highly selective inhibitors of the synthesis of bacterial cell wall. They are active against growing and propagating bacteria.

The initial step of their action is the specific binding of these antibiotics to penicillin-binding proteins (PBP). About ten of different PBPs are known. Some of them reveal transpeptidation enzyme activity. PBP synthesis is controlled by nucleoid; therefore, the mutations may change PBP affinity for beta-lactams.

Beta-lactam binding leads to the termination of transpeptidation reaction, resulting in deep inhibition of peptidoglycan synthesis. The molecular mechanism of the blockade of transpeptidation enzymes by beta-lactams ensues from the structural similarity of these antibiotics with peptide acyl-D-alanyl-D-alanine moiety. Inhibition of transpeptidation is followed by lytic enzyme activation with subsequent cell lysis. Thus, beta-lactams are bactericidal antibiotics. Also the bacterial cells with impaired cell wall (protoplasts, spheroplasts) are abnormally sensitive to phagocytosis.

Penicillins and cephalosporins are of the most potent antibiotics. Beta-lactams possess very weak direct toxicity comparing with other drugs, but they can readily provoke hypersensitivity with allergic reactions. All penicillins render cross-sensitization and cross-reactivity.

Carbapenems, a new modern group of highly active beta-lactams, are devoid of many side effects of penicillins and cephalosporins. Imipenem and meropenem pertain to this drug group. They develop strong activity against many gram-negative and gram-positive bacteria, as well as against anaerobes.

Resistance to beta-lactam antibiotics arises mainly from the microbial synthesis of penicillin- or cephalosporin-degrading enzymes (beta-lactamases). They break down the bonds within the beta-lactam ring conferring microbial resistance to beta-lactams.

Extended-spectrum beta-lactamases additionally degrade third-generation cephalosporins (ceftazidime, cefotaxime) or monobactams.

Zn-containing metallo-beta-lactamases are capable of destroying carbapenems.

Clavulanic acid, sulbactam and tazobactam are irreversible beta-lactamase inhibitors that block enzyme activity. Combined antibiotic antimicrobial agents (e.g., amoxycillin+clavulanic acid) overcome beta-lactamase resistance showing high activity against beta-lactamase-producing bacteria.

β-Lactamase production is usually related to plasmid control. Nevertheless, the serious threat for public health has arisen from the strains of methicillin resistant Staphylococcus aureus (or MRSA) The strains of MRSA originated from chromosome-dependent alteration of staphylococcal penicillin-binding proteins (PBP). These bacteria produce modified protein PBP2a with low affinity to beta-lactam antibiotics. It is encoded by chromosomal gene mecA.

It was found that staphylococcal unresponsiveness to methicillin confers their resistance to almost all of beta-lactams. Last decades MRSA have become a tremendous problem for health care settings as they generate numerous life-threatening infections resistant to beta-lactam therapy.

Some other drugs, including glycopeptides vancomycin and teicoplanin as well as bacitracin and novobiocin, inhibit early steps in the biosynthesis of peptidoglycan. Since these steps are reproduced inside the cytoplasmic membrane, these drugs must initially penetrate the bacterial envelope. As an example, vancomycin is highly efficient, but against gram-positive bacteria only. It remains as the a drug of last resort for treatment of resistant gram-positive bacteria, e.g., MRSA strains.