Differential gene expression in a Bacteroides fragilis metronidazole-resistant mutant

Diniz, Cláudio Galuppo; Farias, Luiz M.; Carvalho, Maria Auxiliadora Roque de; Rocha, Edson R.; Smith, C. Jeffrey

doi:10.1093/jac/dkh256

Cited by 70 publications

(83 citation statements)

References 33 publications

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“…Resistance is generally attributed to changes in the nim genes or associated genes (e.g., IS) (30,56,75,259). The nim gene can be "silent" unless activated by IS elements (111).…”

Section: Continued On Facing Pagementioning

confidence: 99%

Bacteroides: the Good, the Bad, and the Nitty-Gritty

2007

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SUMMARY Summary: Bacteroides species are significant clinical pathogens and are found in most anaerobic infections, with an associated mortality of more than 19%. The bacteria maintain a complex and generally beneficial relationship with the host when retained in the gut, but when they escape this environment they can cause significant pathology, including bacteremia and abscess formation in multiple body sites. Genomic and proteomic analyses have vastly added to our understanding of the manner in which Bacteroides species adapt to, and thrive in, the human gut. A few examples are (i) complex systems to sense and adapt to nutrient availability, (ii) multiple pump systems to expel toxic substances, and (iii) the ability to influence the host immune system so that it controls other (competing) pathogens. B. fragilis, which accounts for only 0.5% of the human colonic flora, is the most commonly isolated anaerobic pathogen due, in part, to its potent virulence factors. Species of the genus Bacteroides have the most antibiotic resistance mechanisms and the highest resistance rates of all anaerobic pathogens. Clinically, Bacteroides species have exhibited increasing resistance to many antibiotics, including cefoxitin, clindamycin, metronidazole, carbapenems, and fluoroquinolones (e.g., gatifloxacin, levofloxacin, and moxifloxacin).

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“…Resistance is generally attributed to changes in the nim genes or associated genes (e.g., IS) (30,56,75,259). The nim gene can be "silent" unless activated by IS elements (111).…”

Section: Continued On Facing Pagementioning

confidence: 99%

Bacteroides: the Good, the Bad, and the Nitty-Gritty

2007

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“…Furthermore, metronidazole-resistant strains can be easily induced from nim-negative B. fragilis (20). Thus, although nim-based resistance is generally considered the most important mechanism of resistance to metronidazole in Bacteroides species, it is already acknowledged that other mechanisms are involved, such as increased efflux gene transcription levels, altera-tions in the DNA repair system, metabolic changes, and lack of activation of the metronidazole molecule (21)(22)(23)(24).…”

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confidence: 99%

Two Multidrug-Resistant Clinical Isolates of Bacteroides fragilis Carry a Novel Metronidazole Resistance nim Gene ( nimJ )

Husain¹,

Veeranagouda

Hsi

et al. 2013

Antimicrob Agents Chemother

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dTwo multidrug-resistant Bacteroides fragilis clinical isolates contain and express a novel nim gene, nimJ, that is not recognized by the "universal" nim primers and can confer increased resistance to metronidazole when introduced into a susceptible strain on a multicopy plasmid. HMW615, an appendiceal isolate, contains at least two copies of nimJ on its genome, while HMW616, an isolate from a patient with sepsis, contains one genomic copy of nimJ. B. fragilis NimJ is phylogenetically closer to Prevotella baroniae NimI and Clostridium botulinum NimA than to the other known Bacteroides Nim proteins. The predicted protein structure of NimJ, based on fold recognition analysis, is consistent with the crystal structures derived for known Nim proteins, and specific amino acid residues important for substrate binding in the active site are conserved. This study demonstrates that the "universal" nim primers will not detect all nim genes with the ability to confer metronidazole resistance, but nimJ alone cannot account for the very high metronidazole MICs of these resistant clinical isolates.

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“…In our study, no nim gene was amplified from any of the 30 isolates exhibiting reduced susceptibility to metronidazole after 48 h of incubation and/or isolates that presented slowly growing resistant subpopulations. This suggests that other potential resistance mechanisms may exist for these isolates, such as decreased pyruvate:ferredoxin oxidoreductase activity, overexpression of efflux pumps, or alterations of the rhamnose catabolism pathway (7,10,28,29,31). However, a potentially novel nim gene, nimI, was present and silent in 7 of the 158 remaining clinical isolates, for which neither increased initial MICs nor slowly growing resistant populations were observed.…”

Section: Discussionmentioning

confidence: 99%

Metronidazole Resistance in Prevotella spp. and Description of a New nim Gene in Prevotella baroniae

Alauzet

Mory

Teyssier

et al. 2010

Antimicrob Agents Chemother

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Nonduplicate clinical isolates of Prevotella spp. recovered from patients hospitalized between 2003 and 2006in two French tertiary-care teaching hospitals were investigated for their susceptibility to metronidazole and the presence of nim genes. Of the 188 strains tested, 3 isolates displayed reduced susceptibility to metronidazole after 48 h of incubation, while 27 additional isolates exhibited heterogeneous resistance after prolonged incubation; all 30 of the isolates were nim negative. Among the remaining 158 isolates, 7 nim-positive isolates were detected. All of these strains were identified as Prevotella baroniae by 16S rRNA gene sequence analysis and contained a new nim gene, named nimI, as determined by DNA sequence analysis. Chromosomal localization of this single-copy gene was demonstrated in all clinical isolates as well as in type strain P. baroniae DSM 16972 by using Southern hybridization. No known associated insertion sequence elements were detected upstream of the nimI gene in any of the nim-positive strains by PCR mapping. After prolonged exposure to metronidazole, stable resistant subpopulations could be selected in nimI-positive Prevotella isolates (n ‫؍‬ 6) as well as in nim-negative Prevotella isolates (n ‫؍‬ 6), irrespective of their initial susceptibility to this antibiotic. This study is the first description of a new nitroimidazole resistance gene in P. baroniae which seems to be silent and which might be intrinsic in this species. Moreover, our findings highlight the fact that high-level resistance to metronidazole may be easily induced in both nim-positive and nim-negative Prevotella sp. strains.

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Differential gene expression in a Bacteroides fragilis metronidazole-resistant mutant

Abstract: Overall, the data indicated that there were global changes in the regulation of the physiology of the metronidazole-resistant strain. In addition, flavodoxin was identified as an important contributor to metronidazole sensitivity in B. fragilis.

Cited by 70 publications

References 33 publications

Bacteroides: the Good, the Bad, and the Nitty-Gritty

Bacteroides: the Good, the Bad, and the Nitty-Gritty

Two Multidrug-Resistant Clinical Isolates of Bacteroides fragilis Carry a Novel Metronidazole Resistance nim Gene ( nimJ )

Metronidazole Resistance in Prevotella spp. and Description of a New nim Gene in Prevotella baroniae

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