Towards an Understanding of Chromosomally Mediated Penicillin Resistance in
            <i>Neisseria gonorrhoeae</i>
            : Evidence for a Porin-Efflux Pump Collaboration

Shafer, William M.; Folster, Jason P.

doi:10.1128/jb.188.7.2297-2299.2006

Cited by 29 publications

(21 citation statements)

References 18 publications

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“…Low-level MDR is mediated by mutations in genes encoding porins or efflux pumps (15,633). In fact, simultaneous porin mutation and RND pump overproduction are needed for gonococcal penicillin or ceftriaxone resistance, again supporting the significance of the synergistic interplay between the OM and efflux pumps (634)(635)(636). Mutations in the "multiple transferable resistance" gene (mtrR) had long been associated with MDR in N. gonorrhoeae, with an assumed alteration in OM permeability (15), but the gene was then found to control the expression of MtrCDE, the most characterized RND pump in Neisseria that contributes to resistance to antibiotics (including ␤-lactams, macrolides, and rifampin), detergents, bile salts, gonadal steroidal hormones, as well as host cationic peptides (15,633,(635)(636)(637)(638)(639).…”

Section: Neisseria Sppmentioning

confidence: 98%

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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Section: Neisseria Sppmentioning

confidence: 98%

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

2015

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“…Other mutations at these positions have been identified in resistant clinical isolates from a separate study, emphasizing the importance of these residues in the penicillinresistant phenotype 54,56 . substitution of these amino-acid residues using targeted mutagenesis has clearly shown that they have a role in antibiotic diffusion 55,57 . both clinical and in vitro studies have reported that aberrant or modified P. aeruginosa OprD porin is linked to carbapenem resistance, with or without the production of a carbapenem hydrolyzing enzyme 58,59 .…”

Section: Nature Reviews | Microbiologymentioning

confidence: 99%

The porin and the permeating antibiotic: a selective diffusion barrier in Gram-negative bacteria

2008

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“…Thus, acquisition of a penA mosaic allele or single amino acid alterations of A501 or possibly G545 and P551 in PBP2 result in a lower affinity for ESCs (1, 16, 18, 19, 23, 25, 32, 38, 43, 45, 48-51, 55, 56, 62). Mutations in the promoter and/or coding sequence of mtrR result in the overexpression of the MtrC-MtrD-MtrE efflux pump (mtrR resistance determinant), which further increases the MICs of ESCs (16, 17, 23, 25, 32, 37, 48-51, 54, 61, 62), and porB1b mutations that alter amino acid G101 and A102 in the PorB1b porin (the penB resistance determinant) result in additionally increased MICs of ESCs (16,23,25,32,34,35,37,(48)(49)(50)(51)62). At least one nontransformable resistance determinant remains unknown (16,25,32,45,62).…”

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confidence: 99%

In Vitro Activity of Ertapenem versus Ceftriaxone against Neisseria gonorrhoeae Isolates with Highly Diverse Ceftriaxone MIC Values and Effects of Ceftriaxone Resistance Determinants: Ertapenem for Treatment of Gonorrhea?

Unemo

Golparian

Limnios

et al. 2012

Antimicrob Agents Chemother

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dClinical resistance to the currently recommended extended-spectrum cephalosporins (ESCs), the last remaining treatment options for gonorrhea, is being reported. Gonorrhea may become untreatable, and new treatment options are crucial. We investigated the in vitro activity of ertapenem, relative to ceftriaxone, against N. gonorrhoeae isolates and the effects of ESC resistance determinants on ertapenem. MICs were determined using agar dilution technique or Etest for international reference strains (n ‫؍‬ 17) and clinical N. gonorrhoeae isolates (n ‫؍‬ 257), which included the two extensively drug-resistant (XDR) strains H041 and F89 and additional isolates with high ESC MICs, clinical ESC resistance, and other types of clinical high-level and multidrug resistance (MDR). Genetic resistance determinants for ESCs (penA, mtrR, and penB) were sequenced. In general, the MICs of ertapenem (MIC 50 ‫؍‬ 0.032 g/ml; MIC 90 ‫؍‬ 0.064 g/ml) paralleled those of ceftriaxone (MIC 50 ‫؍‬ 0.032 g/ml; MIC 90 ‫؍‬ 0.125 g/ml). The ESC resistance determinants mainly increased the ertapenem MIC and ceftriaxone MIC at similar levels. However, the MIC ranges for ertapenem (0.002 to 0.125 g/ml) and ceftriaxone (<0.002 to 4 g/ml) differed, and the four (1.5%) ceftriaxone-resistant isolates (MIC ‫؍‬ 0.5 to 4 g/ml) had ertapenem MICs of 0.016 to 0.064 g/ml. Accordingly, ertapenem had in vitro advantages over ceftriaxone for isolates with ceftriaxone resistance. These in vitro results suggest that ertapenem might be an effective treatment option for gonorrhea, particularly for the currently identified ESC-resistant cases and possibly in a dual antimicrobial therapy regimen. However, further knowledge regarding the genetic determinants (and their evolution) conferring resistance to both antimicrobials, and clear correlates between genetic and phenotypic laboratory parameters and clinical treatment outcomes, is essential.

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Towards an Understanding of Chromosomally Mediated Penicillin Resistance in Neisseria gonorrhoeae : Evidence for a Porin-Efflux Pump Collaboration

Cited by 29 publications

References 18 publications

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

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

The porin and the permeating antibiotic: a selective diffusion barrier in Gram-negative bacteria

In Vitro Activity of Ertapenem versus Ceftriaxone against Neisseria gonorrhoeae Isolates with Highly Diverse Ceftriaxone MIC Values and Effects of Ceftriaxone Resistance Determinants: Ertapenem for Treatment of Gonorrhea?

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