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Protein Synthesis -Translation and Regulation

Molecular Mechanisms of Antibiotic Action on Protein Biosynthesis and Membranes [E

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Semester Paper | Biochemistry for Medics – Lecture Notes

This study demonstrates that the lipopeptide antibiotic friulimicin B acts by an unprecedented, cell wall-directed mechanism. Unlike bacitracin, which prevents dephosphorylation of C55-pyrophosphate, friulimicin B specif-ically forms a complex with the monophosphorylated bactoprenol carrier without affecting membrane integrity. To our knowledge, there is no antibiotic on the market or in clinical development that shares this activity. The clear difference from the molecular mechanisms of daptomycin is also encouraging with regard to the potential development of cross-resistances, since the occurrence of reduced daptomycin susceptibility in S. aureus has already been reported (). Generally, targets such as the sugar-pyrophosphate moiety in lipid II, which is recognized by many lantibiotics (), and the friulimicin target C55-P described here cannot be altered as easily as protein targets, more-variable sugar moieties, or the -Ala--Ala terminus of lipid II. However, the occurrence of vancomycin-intermediate S. aureus strains and strains with reduced susceptibility to daptomycin (), as well as experimental training of strains toward vancomycin () or lantibiotic resistance (), clearly shows that it is within the physiological capacity of bacteria to adequately respond to such antibiotic stresses and to eventually acquire resistance of sufficient levels for clinical treatment failure. Such adaptation may be more difficult to reach with antibiotics that have complex modes of action based on several killing mechanisms, such as described for the pore-forming and cell wall biosynthesis inhibitory lantibiotics (, ). Therefore, it appears an interesting strategy to search for new natural products with such properties, e.g., some glycopeptide antibiotics like telavancin, dalbavancin, and oritavancin (, ), or eventually set out to design such multifunctional antibiotics on a rational basis when more information on molecular mechanisms and targets is available ().

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In this study, we set out to identify the molecular target and the specific mechanism of action of the lipopeptide antibiotic friulimicin B. We found it to form a complex with bactoprenol phosphate without affecting membrane integrity.

Molecular mechanisms of membrane targeting …

Molecular Mechanisms of Antibiotic Action on Protein Biosynthesis and Membranes: E

While our results clearly demonstrate that, in spite of sharing some structural features, friulimicin and daptomycin differ in the molecular mode of antibiotic action, they unfortunately do not provide any hints as to a molecular target for daptomycin in the cell wall biosynthesis pathway, particularly in the membrane-associated steps. Such activities had been suggested in early work on daptomycin (, , ) and by transcriptional profile analysis of daptomycin-treated S. aureus cells (). In addition, comparative transcriptomic and proteomic analysis of friulimicin versus daptomycin with B. subtilis supported such a view (), although this study also identified differences in the response patterns which point toward distinctions between their antibiotic activities on the molecular level.

Many active efflux systems resemble other transport proteins that catalyze the efflux of common, small molecules, like glucose or cations, and it is likely that mutation has modified them to transport antibiotics. Based on their overall structure, mechanism, and sequence homologies, these transport proteins are classified into four families: (1) the major facilitator family; (2) the resistance nodulation division family; (3) the staphylococcal multidrug resistance family; and (4) the ATP-binding cassette (ABC) transporters. Of these four families, only the ABC transporters use the chemical energy generated from the hydrolysis of ATP to drive molecules across the membrane. Members of the three other families use an electrochemical proton gradient, or proton-motive force, as the source of energy (18, 19).

of cell wall biosynthesis for potent antibiotic ..

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. Mechanism of action of beta-lactam antibiotics. Top: In the absence of drug, transpeptidase enzymes (PBPs) in the cell wall catalyze cross-links between adjacent glycan chains, which involves the removal of a terminal D-alanine residue from one of the peptidoglycan precursors. Glycosyltransferases (GT), which exist as either separate subunits, or tightly associated with transpeptidases (e.g. as is the case for PBP-2) create covalent bonds between adjacent sugar molecules NAM & NAG. The net result of covalent bonds between both the peptide and sugar chains creates a rigid cell wall that protects the bacterial cell from osmotic forces that would otherwise result in cell rupture. Bottom: Beta-lactam antibiotics, which include penicillins (Pen), cephalosporins (Ceph), monobactams (Mono) and carbapenems (Carba) bear a structural resemblance to the natural D-Ala-D-Ala substrate for the transpeptidase, and exert their inhibitory effects on cell wall synthesis by tightly binding to the active site of the transpeptidase (PBP). NAG: N-acetylglucosamine; NAM: N-acetylmuramic acid. Structure of PBP adapted from Mcstrother ().

Antibiotics are a collection of natural products and synthetic compounds that kill bacteria. Naturally occurring antibiotics are isolated from molds, yeasts, and bacteria. These organisms use antibiotics as defense mechanisms to kill other bacteria. Alternatively, synthetic antibiotics are developed by understanding the architecture and function of bacteria (see Fig. 1). Some bacteria have cell walls, and many effective antibiotics, such as penicillin, bacitracin, and cephalosporin, inhibit the synthesis of this cell wall. The bacterial machinery for protein biosynthesis differs from that of many host organisms and, therefore, is a good target for antibiotics, such as tetracycline and chloramphenicol. Additionally, antibiotics, such as rifampin and quinolones, specifically inhibit DNA replication in bacteria (1).

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The bacterial cell wall has a lattice-like structure due to the cross-linking of both chains of sugar molecules (N-acetylmuramic acid & N-acetylglucosamine) and polypeptide chains (). The building blocks that make up the cell wall (like individual bricks for constructing a wall) are synthesized inside the bacterial cell, and then transported outward through the cell membrane and assembled by enzymes that covalently link the amino acid chains (transpeptidases) and sugar chains (glycosyltransferases). Both of these enzymes are targets for inhibition by different antibiotic agents (beta-lactams & glycoproteins).

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Enveloped by effective barriers, bacteria use pore-forming proteins, called porins, to obtain nutrients from outside the cell. Porins are transmembrane proteins that function as nonspecific, aqueous channels, and allows nutrients to diffuse across the membrane. Porins generally exclude antibiotics because they are narrow and restrictive. Most antibiotics are large, uncharged molecules that cannot easily traverse the narrow porin channels that are lined with charged amino acid residues. However, some antibiotics enter the bacteria through porins, and the deletion or alteration of these porins to exclude particular antibiotics is linked to antibiotic resistance.

Catalog Record: International Symposium on Deterioration ..

Because bacteria cannot develop barriers that are impermeable to all molecules, some toxins do diffuse into bacteria along with nutrients. Therefore, bacterial cell membranes also contain transport proteins that cross the membranes and use energy to remove toxins. They are called active efflux systems, and some are directly identified as another significant cause of antibiotic resistance.

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