2. A review of the molecular mechanisms of drug efflux in pathogenic bacteria: A structure-function perspective

In book: Recent Research Developments in Membrane Biology, Chapter: A review of the molecular mechanisms of drug efflux in pathogenic bacteria: A structure-function perspective, Publisher: Research Signpost, Inc., Editors: P. Shankar, pp.15-66

ABSTRACT Pathogenic and opportunistic bacteria which are causative agents of infectious disease and harbor effective drug resistance mechanisms may confound treatment in human clinical medicine. Of the various antimicrobial agent resistant mechanisms, active efflux by secondary active transporter systems, called drug efflux pumps, are commonly found within infectious disease causing bacteria. These secondary active drug efflux systems are energized by cation gradients and may have single or multiple drug substrates. It is these multidrug efflux systems that compromise chemotherapeutic efforts against multiple drug resistant bacteria. Close scrutiny of these multidrug efflux systems may provide useful molecular information for potential modulation in order to reduce the conditions that foster bacterial drug resistance and thus possibly restore clinical efficacy of antimicrobial agents. This chapter focuses on key bacterial secondary drug efflux pump systems from a molecular perspective.

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    ABSTRACT: Pathogenic strains of Vibrio cholerae are responsible for endemic and pandemic outbreaks of the disease cholera. The complete toxigenic mechanisms underlying virulence in Vibrio strains are poorly understood The hypothesis of this work was that virulent versus non-virulent strains of V. cholerae harbor distinctive genomic elements that encode virulence. The purpose of this study was to elucidate genomic differences between the O1 serotypes and non-O1 V. cholerae PS15, a non-toxigenic strain, in order to identify novel genes potentially responsible for virulence. In this study, we compared the whole genome of the non-O1 PS15 strain to the whole genomes of toxigenic serotypes at the phylogenetic level, and found that the PS15 genome was distantly related to those of toxigenic V. cholerae. Thus we focused on a detailed gene comparison between PS15 and the distantly related O1 V. cholerae N16961. Based on sequence alignment we tentatively assigned chromosome numbers 1 and 2 to elements within the genome of non-O1 V. cholerae PS15. Further, we found that PS15 and O1 V. cholerae N16961 shared 98% identity and 766 genes, but of the genes present in N16961 that were missing in the non-O1 V. cholerae PS15 genome, 56 were predicted to encode not only for virulence–related genes (colonization, antimicrobial resistance, and regulation of persister cells) but also genes involved in the metabolic biosynthesis of lipids, nucleosides and sulfur compounds. Additionally, we found 113 genes unique to PS15 that were predicted to encode other properties related to virulence, disease, defense, membrane transport, and DNA metabolism. Here, we identified distinctive and novel genomic elements between O1 and non-O1 V. cholerae genomes as potential virulence factors and, thus, targets for future therapeutics. Modulation of such novel targets may eventually enhance eradication efforts of endemic and pandemic disease cholera in afflicted nations. Mukherjee M, Kakarla P, Kumar S, Gonzalez E, Floyd JT, Inupakutika M, Devireddy AR, Tirrell SR, Bruns M, He G, Lindquist IE, Sundararajan A, Schilkey FD, Mudge J and Varela MF. Comparative genome analysis of non-toxigenic non-O1 versus toxigenic O1 Vibrio cholerae. Genomics Discov. 2014; 2:1.
    Genomics discovery. 06/2014; 2(1):1-15.


Available from
May 21, 2014