gyrA Mutations Associated with Quinolone Resistance in Bacteroides fragilis Group Strains

Abstract

Mutations in the gyrA gene contribute considerably to quinolone resistance in Escherichia coli. Mechanisms for quinolone resistance in anaerobic bacteria are less well studied. The Bacteroides fragilis group are the anaerobic organisms most frequently isolated from patients with bacteremia and intraabdominal infections. Forty-four clinafloxacin-resistant and-susceptible fecal and clinical isolates of the B. fragilis group (eight Bacteroides fragilis, three Bacteroides ovatus, five Bacteroides thetaiotaomicron, six Bacteroides uniformis, and 22 Bacteroides vulgatus) and six ATCC strains of the B. fragilis group were analyzed as follows: (i) determination of susceptibility to ciprofloxacin, levofloxacin, moxifloxacin, and clinafloxacin by the agar dilution method and (ii) sequencing of the gyrA quinolone resistance-determining region (QRDR) located between amino acid residues equivalent to Ala-67 through Gln-106 in E. coli. Amino acid substitutions were found at hotspots at positions 82 (n ‫؍‬ 15) and 86 (n ‫؍‬ 8). Strains with Ser82Leu substitutions (n ‫؍‬ 13) were highly resistant to all quinolones tested. Mutations in other positions of gyrA were also frequently found in quinolone-resistant and -susceptible isolates. Eight clinical strains that lacked mutations in their QRDR were susceptible to at least two of the quinolones tested. Although newer quinolones have good antimicrobial activity against the B. fragilis group, quinolone resistance in B. fragilis strains can be readily selected in vivo. Mutational events in the QRDR of gyrA seem to contribute to quinolone resistance in Bacteroides species.

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

“…Quinolones inhibit two specific enzymes, DNA gyrase and DNA topoisomerase IV, which aid in bacterial DNA replication, and mutations in these enzymes are the most common causes of quinolone resistance. Mutations in GyrA causing fluoroquinolone resistance in B. fragilis have been identified at hot-spot positions 82 and 86 (equivalent to positions 83 and 87 in E. coli) (174,213). Substitutions in GyrB, ParC, and ParE have so far proven uncommon and are not well established in B. fragilis.…”

Antianaerobic Activity of a Novel Fluoroquinolone, WCK 771, Compared to Those of Nine Other Agents

“…Newer quinolones with increased antianaerobic activity include (i) those with slightly increased activity against aerobic gram-positive and some nonfermentative gram-negative bacteria (sparfloxacin, grepafloxacin, and levofloxacin) and (ii) those with significantly improved antianaerobic activity (garenoxacin, clinafloxacin, and sitafloxacin are the most active, followed by trovafloxacin, moxifloxacin, and gatifloxacin) (5-9, 11, 12, 18, 20). Development and/or marketing of many of the latter quinolones has been discontinued.During the past few years, several reports on quinoloneresistant anaerobic strains with defined quinolone resistance mechanisms (efflux or type II topoisomerase mutations) have been published (4,14,15,17). Plasmid-mediated complementation of gyrA and gyrB in quinolone-resistant B. fragilis has also been described (16).…”

“…During the past few years, several reports on quinoloneresistant anaerobic strains with defined quinolone resistance mechanisms (efflux or type II topoisomerase mutations) have been published (4,14,15,17). Plasmid-mediated complementation of gyrA and gyrB in quinolone-resistant B. fragilis has also been described (16).…”

Genetic Determinant of Intrinsic Quinolone Resistance in Fusobacterium canifelinum

“…Two main mechanisms are associated with resistance: (i) alteration of target enzymes (gyrase and topoisomerase IV) caused by single or stepwise chromosomal mutations in encoding genes and (ii) reduced intracellular accumulation due to increased efflux of the drug (20). The increasing emergence of resistance among anaerobes, namely, B. fragilis and Clostridium difficile, may be a consequence of previous widespread use of quinolones, which may have enriched first-step mutants in the intestinal tract (1,21). Quinolone resistance in the B. fragilis group strains is strongly correlated with amino acid substitutions at positions 82 and 86 in GyrA (equivalent to positions 83 and 87 of E. coli).…”

“…1), with three being silent (CTA to TTA [both coding for L], GCA to GCT [both coding for A], and GTA to GTT [both coding for V]). Relevant for the level of resistance is the TCA-to-TTA mutation replacing Ser79 (polar amino acid, equivalent to Escherichia coli Ser83 and Bacteroides fragilis Ser82) with leucine, a hydrophobic and aliphatic amino acid (16,(21)(22)(23). In addition, by mutation of GGA to AGA, Gly83 (hydrophobic, equivalent to Asp87 in quinolonesusceptible E. coli strains) in F. nucleatum subsp.…”