Alterations of susceptibility of Pseudomonas aeruginosa by overproduction of multidrug efflux systems, MexAB-OprM, MexCD-OprJ, and MexXY/OprM to carbapenems: Substrate specificities of the efflux systems

Okamoto, Kyoichi; Gotoh, Naomasa; Nishino, Takeshi

doi:10.1007/s10156-002-0193-7

Cited by 58 publications

(45 citation statements)

References 14 publications

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“…In the case of the fluoroquinolones, the overall hydrophilicity (3,63) and bulk (26,33,34) of these compounds affect their sensitivity to specific efflux pumps, and the apparent structure-activity relationships delineated have contributed in the identification of novel development candidates that are less prone to efflux (49). Finally, studies of the effects of overexpression of the MexAB-OprM, MexCD-OprJ, and MexXYOprM systems on the efflux of a series of closely related carbapenem-class antibiotics has revealed intricate substrate specificities that could be further exploited in directed chemistry efforts (48). Hence, overall, there seems a reasonable expectation that targeted medicinal chemistry efforts may be undertaken to circumvent specific efflux mechanisms that limit the intracellular accumulation and therein activity of antibacterial discovery leads identified through screens employing efflux-defective strains.…”

Section: Discussionmentioning

confidence: 99%

A Novel Indole Compound That Inhibits Pseudomonas aeruginosa Growth by Targeting MreB Is a Substrate for MexAB-OprM

Robertson¹,

Doyle²,

Du³

et al. 2007

J Bacteriol

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Drug efflux systems contribute to the intrinsic resistance of Pseudomonas aeruginosa to many antibiotics and biocides and hamper research focused on the discovery and development of new antimicrobial agents targeted against this important opportunistic pathogen. Using a P. aeruginosa PAO1 derivative bearing deletions of opmH, encoding an outer membrane channel for efflux substrates, and four efflux pumps belonging to the resistance nodulation/cell division class including mexAB-oprM, we identified a small-molecule indole-class compound (CBR-4830) that is inhibitory to growth of this efflux-compromised strain. Genetic studies established MexAB-OprM as the principal pump for CBR-4830 and revealed MreB, a prokaryotic actin homolog, as the proximal cellular target of CBR-4830. Additional studies establish MreB as an essential protein in P. aeruginosa, and efflux-compromised strains treated with CBR-4830 transition to coccoid shape, consistent with MreB inhibition or depletion. Resistance genetics further suggest that CBR-4830 interacts with the putative ATP-binding pocket in MreB and demonstrate significant cross-resistance with A22, a structurally unrelated compound that has been shown to promote rapid dispersion of MreB filaments in vivo. Interestingly, however, ATP-dependent polymerization of purified recombinant P. aeruginosa MreB is blocked in vitro in a dosedependent manner by CBR-4830 but not by A22. Neither compound exhibits significant inhibitory activity against mutant forms of MreB protein that bear mutations identified in CBR-4830-resistant strains. Finally, employing the strains and reagents prepared and characterized during the course of these studies, we have begun to investigate the ability of analogues of CBR-4830 to inhibit the growth of both efflux-proficient and efflux-compromised P. aeruginosa through specific inhibition of MreB function.The activity of efflux-based drug extrusion mechanisms impact the overall effectiveness of current antimicrobial therapies and impair efforts to discover new chemotherapeutic treatments for many serious bacterial diseases (4,42,43,65). Few bacterial pathogens exemplify the importance of the interplay between xenobiotic efflux extrusion systems and the exclusion of antimicrobial agents at the level of the poorly permeable gram-negative outer membrane quite like Pseudomonas aeruginosa (46, 58). Indeed, this organism has the capacity to encode more than 50 potential multidrug transporters including 12 resistance nodulation/cell division (RND)-class transporters, which to date, represent the only clinically significant drug transporters that have been experimentally validated for P. aeruginosa (20,58).The MexAB-OprM tripartite pump confers basal resistance to P. aeruginosa to a number of chemically distinct antibiotics (58) and through gain-of-function mutations, including those in regulatory proteins (e.g., mexR or mexZ), may overproduce MexAB-OprM or other RND-class pumps which are significant contributors to multidrug resistance in clinical P. areuginosa isolates...

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Section: Discussionmentioning

confidence: 99%

A Novel Indole Compound That Inhibits Pseudomonas aeruginosa Growth by Targeting MreB Is a Substrate for MexAB-OprM

Robertson¹,

Doyle²,

Du³

et al. 2007

J Bacteriol

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“…Synergistic interactions are expected to occur when multicomponent efflux pumps (e.g., RND systems) and singlet pumps (e.g., TetA/C) operate coordinately to extrude substrates from both the cytoplasm and the periplasmic space up to the external medium (25). Since MexAB-OprM is able to accommodate some carbapenems such as meropenem (252,402,430,432), its contribution to the acquired resistance of clinical strains to these agents was investigated and found to be modest with respect to other mechanisms such as the loss of OprD and carbapenemase production (380,381,383,384). Thus, the role of the pump appears to be obscured by more efficient drug-specific resistance mechanisms in terms of the resistance phenotype of the mutants.…”

Section: Pseudomonas Aeruginosamentioning

confidence: 99%

The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

2015

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SUMMARY The global emergence of multidrug-resistant Gram-negative bacteria is a growing threat to antibiotic therapy. The chromosomally encoded drug efflux mechanisms that are ubiquitous in these bacteria greatly contribute to antibiotic resistance and present a major challenge for antibiotic development. Multidrug pumps, particularly those represented by the clinically relevant AcrAB-TolC and Mex pumps of the resistance-nodulation-division (RND) superfamily, not only mediate intrinsic and acquired multidrug resistance (MDR) but also are involved in other functions, including the bacterial stress response and pathogenicity. Additionally, efflux pumps interact synergistically with other resistance mechanisms (e.g., with the outer membrane permeability barrier) to increase resistance levels. Since the discovery of RND pumps in the early 1990s, remarkable scientific and technological advances have allowed for an in-depth understanding of the structural and biochemical basis, substrate profiles, molecular regulation, and inhibition of MDR pumps. However, the development of clinically useful efflux pump inhibitors and/or new antibiotics that can bypass pump effects continues to be a challenge. Plasmid-borne efflux pump genes (including those for RND pumps) have increasingly been identified. This article highlights the recent progress obtained for organisms of clinical significance, together with methodological considerations for the characterization of MDR pumps.

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“…Bacteria such as Escherichia coli and Pseudomonas aeruginosa have been found to be extensively resistant to ciprofloxacin and fluoroquinolones due to the overexpression of proteins involved in the efflux pump system powered by the hydrogen ion gradient [30][31]. Rather than having an efflux pump system customized with antibiotic specificity, bacteria such as MRSA and P. aeruginosa express non-specific multidrug resistance pumps which efflux a range of antibiotics including the β-lactam antibiotics, as shown in figure 5 [32][33][34]. The reduction of permeability in the outer membrane of bacteria is another strategy employed ( Figure 6).…”

Section: Antibiotic Efflux Pump and Reduced Permeabilitymentioning

confidence: 99%

Untitled

2019

Org.Commun.

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Antibiotic resistance had first been reported not long after the discovery of the first antibiotic and has remained a major public health issue ever since. Challenges are constantly encountered during the mitigation process of antibiotic resistance in the clinical setting; especially with the emergence of the formidable superbug, a bacteria with multiple resistance towards different antibiotics; this resulted in the term multidrug resistant (MDR) bacteria. This rapid evolution of the resistance phenomenon has propelled researchers to continuously uncover new antimicrobial agents in a bid to hopefully, downplay the rate of evolution despite a drying pipeline. Recently, there has been a paradigm shift in the mining of potential antimicrobials; in the past, targets for drug discovery were from microorganisms and at current, the focus has moved onto plants, this is mainly due to the beneficial attributes that plants are able to confer over that of microorganisms. This review will briefly discuss antibiotic resistance mechanisms employed by resistant bacteria followed by a detailed expository regarding the use of secondary metabolites from plants as a potential solution to the MDR pathogen. Finally, future prospects recommending enhancements to the usage of plant secondary metabolites to directly target antibiotic resistant pathogens will be discussed.

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Alterations of susceptibility of Pseudomonas aeruginosa by overproduction of multidrug efflux systems, MexAB-OprM, MexCD-OprJ, and MexXY/OprM to carbapenems: Substrate specificities of the efflux systems

Cited by 58 publications

References 14 publications

A Novel Indole Compound That Inhibits Pseudomonas aeruginosa Growth by Targeting MreB Is a Substrate for MexAB-OprM

A Novel Indole Compound That Inhibits Pseudomonas aeruginosa Growth by Targeting MreB Is a Substrate for MexAB-OprM

The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

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