Macrolide antibiotics resistance mechanisms

Macrolide antibiotics target the bacterial ribosome and inhibit the bacterial protein biosynthesis. Many gram-negative bacteria are inherently resistant to mac-rolides because their outer membrane is impermeable to macrolides. Several mechanisms of acquired resistance have been reported. In some cases, resistance is conferred by methylation of ribosomes by methylase enzymes, the genes of... 

The resistance mechanisms that cause the inactivation of penicillins, cephalosporins, aminoglycosides, macrolides and tetracyclines do not apply to fluoroquinolones, and there is therefore no cross-resistance between quinolones and other antibiotics. 

Plasmid (or transposon)-encoded enzymes are thus responsible for the degradation of several different types of antibiotics. The inactivation of several /J-lactams, AGACs, 14-membered macrolides, other macrolides, lin-cosamides and streptogramis (MLS) and chloramphenicol is a major resistance mechanism it has yet to be shown that inactivation of other antibiotics falls into this category. 

The MLS (macrolides, lincosamides, streptogramins) group of antibiotics all inhibit protein synthesis by binding to the 50S ribosomal subunit. Resistance mechanisms specific to individual members occur but resistance to all may be conferred by a single mechanism that involves 23S rRNA. However, it is claimed that the quinupristin-dalfopristin combination does not demonstrate cross-resistance to other antibiotics within the MLS group or to other antibiotics. 

Clindamycin binds exclusively to the 50S subunit of bacterial ribosomes and suppresses protein synthesis. Although clindamycin, erythromycin, and chloramphenicol are not structurally related, they act at sites in close proximity, and binding by one of these antibiotics to the ribosome may inhibit the interaction of the others. There are no clinical indications for the concurrent use of these antibiotics. Macrolide resistance due to ribosomal methylation by encoded enzymes also may produce resistance to clindamycin. However, because cUndamycin does not induce the methylase, there is cross-resistance only if the enzyme is produced con-stitutively. Clindamycin is not a substrate for macrolide efflux pumps thus, strains that are resistant to macrolides by this mechanism are susceptible to clindamycin. Altered metabolism occasionally causes clindamycin resistance. 

Nakajima, Y. (1999). Mechanisms of bacterial resistance to macrolide antibiotics. J. Infect. Chemother. 5,61—74. 

In this chapter, the molecular-biological mode of action of macrolide antibiotics and the biochemical and genetic mechanisms of resistance to MLS antibiotics are reviewed. Based on a recent X-ray crystallographic study on a 50S ribosomal subunit from Haloarcula marismortui and the finding of intracellular macrolide accumulation, the mode of action from the viewpoint of a new hypothetical concept, deposition binding, and mechanisms of drug resistance in clinically isolated bacteria are discussed. In addition, recent major developments in macrolide antibiotics are briefly described. 

Genes for resistance are not new creations. There seems to be no exception to the rule in genes responsible for resistance to macrolide antibiotics. In fact, many kinds of clinical isolates that carry resistant determinant(s) to macrolide antibiotics rarely develop the same mechanism as drug-resistant mutants, which arise in vitro from treatment with mutagens. 

The molecular biological mode of action of macrolide antibiotics and the biochemical and genetic mechanism of resistance to macrolide, lincosamide, and type B streptogramin antibiotics were reviewed in this chapter. 

The resistance mechanisms are divided into three major groups (1) target modification, (2) decreased macrolide accumulation due to enhanced drug efflux, and (3) inactivation of the antibiotics. 

Corcoran, J. W. (1984), Mode of action and resistance mechanisms of macrolides. In Macrolide Antibiotics Chemistry, Biology, and Practice (S. Omura Ed.), pp. 231-259. Academic Press, Orlando, FL. 

The primary mechanism underlying the resistance of gram-positive organisms to macrolide antibiotics is... 

A more recently recognized mechanism of dmg resistance is that of efflux in which the antibiotic is rapidly extmded horn the cell by an energy-dependent mechanism. This affects antibiotics such as the tetracyclines and macrolides. 

Some streptococci have developed a different mechanism of acquired resistance to penicillin drugs. These bacteria have altered transpeptidases (also known as penicillin-binding proteins) that no longer bind penicillin, and thus peptidoglycan synthesis is not disrupted. This mechanism of resistance is found in Streptococcus pneumoniae. Estimates of penicillin-resistant S. pneumoniae in the United States range from 25% to 66%, including strains recovered from ocular and periocular infections. Many isolates of penicillin-resistant S.pneumoniae also are resistant to the cephalosporins, macrolides, and the older fluoroquinolones. Use of alternative antibiotics such as vancomycin is necessary for infections caused by penicillin-resistant isolates. 

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