Macrolides efflux

Binding of substrates suggests that MFPs might be directly involved in transporting substrates across the periplasm and the outer membrane. The in vitro reconstitution studies support this idea. AcrA stimulates the transport activities of the reconstituted RND transporters AcrB and AcrD [95, 116]. Another MFP MacA is absolutely required for the ATPase activity of MacB, the ABC-type macrolide efflux transporter [122]. 

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. 

Enzymatic mechanisms that inactivate macrolides appear to be rare among clinical isolates compared with mechanisms of phenotypically decreased macrolide accumulation due to either a target site alteration (i.e., ribosome modification) or enhanced macrolide efflux. 

Oancy, J., Dib-Hajj, F., Petitpas, J., and Yuan, W. (1997). Cloning and characterization of a novel macrolide efflux gene, mreA. from Streptococcus agalactiae. Antimicrob. Agents Chemother. 41, 2719-2723. 

The combined intrinsic activities of different efflux pumps play a major role for the intrinsic resistance of Gram-negative bacteria to macrolides and oxazolidi-nones as well as to the intrinsic resistance of Pseudomonas aeruginosa against a broad range of disinfectants and antibiotics. 

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. 

A gene designated msrA has been identified in Staph, aureus which confers resistance to macrolides and streptogramins but not to lincosamides. Its function is unknown but the DNA sequence is homologous to genes coding for known efflux proteins. 

S pneumoniae, S aureus, H influenzae, Moraxella catarrhaiis, mycoplasmas, Legionella, Chlamydia, H pylori, N gonorrhoeae, fragilis, T gondii, and nontuberculosis mycobacteria. Many macrolide-resistant strains are susceptible to ketolides because the structural modification of these compounds renders them poor substrates for efflux pump-mediated resistance and they bind to ribosomes of some bacterial species with higher affinity than macrolides. 

A multidrug efflux system that appears to be a major contributor to intrinsic high-level resistance to aminoglycosides and macrolides has been identified in Burkholderia pseudomallei (133). 

Macrolide Resistance Due to Decreased Accumulation (Enhanced Efflux) in Staphylococci and Streptococci... 

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. 

Wondrack, L., Massa, M., Yang, B. V., and Sutcliffe, J. (1996). Clinical strain of Staphylococcus aureus inactivates and causes efflux of macrolides. Antimicrob. Agents Chemother. 40,992-998. 

Goldman, R. C., and Capobianco, J. O. (1990). Role of an energy-dependent efflux pump in plasmid pNE24-mediated resistance to 14- and 15-membered macrolides in Staphylococcus epidermidis. Antimicrob. Agents Chemother. 34, 1973-1980. 

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