AMINOGLYCOSIDE RESISTANCE BY ALTERED TRANSPORT
In order to gain access to the target ribosomes, aminoglycosides traverse the plasma membrane and, in the case of Gram negative bacteria, the outer membrane as well. Transport across the plasma membrane requires the proton pump systems, and mutants deficient in electron transport chain components are consequently resistant [1-4]. Inactivation of the outer-membrane porin protein OprH in Pseudomonas aeruginosa has been shown to result in gentamicin resistance . This is likely the result of a polar effect on the downstream two-component regulatory system phoP–phoQ. These genes are global regulators of a number of genes including some that are involved in lipopolysaccharide modification, a known modulator of aminoglycoside entry [6-7].
Table 1. Aminoglycosideefflux mediated resistance systems
The RND family of efflux pumps are restricted to gram-negative organisms  and consists of three major components: the RND pump, a periplasmic membrane fusion protein (MFP), and an outer-membrane factor (OMF). These three proteins are able to effectively pump several antibiotics, dyes, and ions depending on the type of RND pump associated with the system.
Bacterial efflux pump. This system is comprised of three essential components; The RND pump (e.g., AcrB and MexX) is located on the cytoplasmic membrane and is responsible for the recognition of substrates in the cytosol, including aminoglycosides, and moving them into the periplasmic space. The membrane fusion protein (MFP) (e.g., AcrA and MexY) is responsible for moving the substrate across the periplasm; the final component is the outer membrane factor (OMF) (e.g., TolC and OprM) that provides a conduit for the substrate to the extracellular region of the cell.
The P. aeruginosa MexXY system is able to effectively pump out a broad range of aminoglycosides resulting in pan-aminoglycoside resistance . The genes mexXY are collocated in an operon with mexZ, which expresses a negative regulator of mexXY. It was originally thought that the OMF associated with MexXY was OprM; however, several other studies have found evidence to show that if the OMFs OprG, OprH, and OprI are not expressed, then the MIC against various aminoglycosides can drop 4- to 16-fold when compared to the wild-type parent strain .
The AcrAD–TolC system in E. coli is homologous to MexXY–OprM and confers efflux-mediated resistance to aminoglycosides . There are a number of AcrD homologs in other members of the Enterobacteriaceae, suggesting that this pan-aminoglycoside resistance system may exist in other gram-negative organisms. The majority of RND pumps like MexAB–OprM and AcrAB–TolC have a multidrug resistance profile and act more effectively against lipophilic and amphiphilic substrates. As a result, the hydrophilic aminoglycosides are poor substrates for these pumps.
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