Biotechnology - Yu.O. Sazykin 2006

Applied Biotechnology
Challenges in the Discovery, Development, and Application of Antibiotics in Medical Practice
Mechanisms of Antibiotic Action — Inhibitors of Microbial Cytoplasmic Membrane Functions

Among the Antibiotics used in clinical practice with this MECHANISM OF ACTION, the best known are antifungal antibiotics with a polyene Structure (i.e., containing conjugated double bonds): nystatin, amphotericin B, and levorin. They interact with sterols in the membrane of pathogenic Fungi and Yeasts, resulting in The formation of pores through which low-molecular-weight metabolites leak out, leading to Cell death. Ergosterol (the primary sterol in fungal and Yeast membranes) reacts with polyene antibiotics faster and at lower concentrations than Cholesterol in animal cell membranes. This reaction underlies the selective action of polyenes. Nevertheless, polyenes are predominantly used for topical and cavitary Applications only.

When examining The Mechanism of action of antibiotics at THE MOLECULAR LEVEL, differences emerge even among Representatives of the same group, i.e., those with a similar mechanism of action.

For example, different Protein Synthesis Inhibitors interact with different ribosomal subunits and with distinct sites on these subunits. Naturally, this suppresses different reactions of such a complex, multi-stage process as protein synthesis. This fact explains why clinics use not just one, but various protein synthesis inhibitors, since their mechanism of action differs at the molecular level.

The second example concerns beta-lactam antibiotics. The cellular targets for Penicillins and Cephalosporins are transpeptidases and D,D-Carboxypeptidases, which catalyze the final reactions in the complex Synthesis of the Introduction/37.html">Bacterial Cell wall polymer, peptidoglycan. The Active Site of these Enzymes has an affinity for The amino acid residues that terminate the peptide chains.

In almost all Bacteria, the last and penultimate Amino Acids in the peptide chain are D-Alanine. The beta-lactam ring in the molecule of antibiotics that inhibit The activity of transpeptidases and D,D-carboxypeptidases resembles one of the stereoconformations assumed by the free end of the peptide chains—which is D-alanyl-D-alanine—upon entering the active site.

Upon entering the active site of the target enzymes, the beta-lactam antibiotic, following the Cleavage of its beta-lactam ring, binds covalently to the enzyme by acylating one of the hydroxyl groups in the active site. The bacterial cell contains several transpeptidases of varying molecular weight, for instance, those involved in peptidoglycan elongation (the growth of rod-shaped Cells), the formation of cell poles, or the creation of the peptidoglycan septum during Cell Division.

Different beta-lactam molecules exhibit varying affinities for different transpeptidases, known as penicillin-binding Proteins (PBPs): PBPs1, PBPs2, PBPs3, etc. Therefore, the mechanism of action of various beta-lactams is actually distinct. All of this directly impacts the therapeutic properties of beta-lactam antibiotics.

The Importance of understanding the Mechanisms of action of antibiotics—specifically beta-lactams—for attending physicians and pharmacists is clearly demonstrated by the fact that foreign pharmaceutical companies frequently include a line in brief promotional Materials intended for a broad audience of practitioners: the new beta-lactam reacts with a specific "penicillin-binding protein" (a particular PBP). Unfortunately, our specialists are insufficiently familiar with this criterion, which determines the duration of a drug's antibiotic effect, its tolerability in certain categories of patients, and other important qualities.

The foregoing underscores the necessity for physicians and pharmacists to understand the fundamentals of antibiotic mechanisms of action.