Metallo-β-Lactamase-Producing Bacteroides Species Can Shield Other Members of the Gut Microbiota from Antibiotics

Abstract

Antibiotics disrupt the intestinal microbiota, rendering patients vulnerable to colonization by exogenous pathogens. Intermicrobial interactions may attenuate this effect. Incubation with ceftriaxone-resistant, ccrA-positive, ␤-lactamase-producing Bacteroides strains raised the minimum bactericidal concentration of ceftriaxone required to kill a susceptible Escherichia coli strain (mean change, <0.25 to 29 mg/liter; P ‫؍‬ 0.009); incubation with ceftriaxone-resistant but non-␤-lactamase-producing Bacteroides strains had no effect. The production of ␤-lactamase by common members of the intestinal microbiota (Bacteroides) can protect susceptible fellow commensals from ␤-lactams. The indigenous anaerobic microbiota of the lower intestinal tract remains a crucial mammalian host defense against colonization by exogenous, potentially pathogenic microorganisms (1-3). This defense mechanism is termed colonization resistance and may be abolished in hospitalized patients by the administration of antibiotic therapy. Antibiotics, including ␤-lactam antibiotics, may disrupt the intestinal microbiota, rendering patients susceptible to colonization or infection with nosocomial pathogens.We previously demonstrated in ␤-lactam-treated mice that oral recombinant proteolysis-resistant ␤-lactamase enzymes that inactivate ␤-lactams can preserve gut colonization resistance against multiple nosocomial pathogens, including vancomycinresistant Enterococcus (VRE), extended-spectrum ␤-lactamaseproducing Klebsiella pneumoniae, and Clostridium difficile (4-6), via intraintestinal degradation of excreted antibiotic by intraluminal ␤-lactamases. This strategy holds promise for the prevention of pathogen colonization in patients treated with parenteral antibiotics, as antibiotic degradation within the colonic lumen does not impact systemic concentrations (7). We also demonstrated that, despite their receipt of parenteral ␤-lactams, mice intestinally colonized with a ␤-lactamase-producing member of the commensal microbiota (Bacteroides thetaiotaomicron) preserved colonization resistance against VRE and C. difficile (8). However, the genetics of ␤-lactam resistance in the protective Bacteroides species in this study were not known, and a comparator anaerobe was not studied. Here, we hypothesized that ceftriaxone-resistant Bacteroides species producing the broad-spectrum metallo-␤-lactamase CcrA would protect ␤-lactam-susceptible members of the microbiota from the ␤-lactam ceftriaxone in vitro, while ceftriaxone-resistant (but non-␤-lactamase-producing) Bacteroides species would not.(Portions of this study were previously presented in abstract form at the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 17 to 20 September 2011.)Bacterial strains. To test the protection of a clinical strain of ceftriaxone-susceptible Escherichia coli (chosen as a representative member of the human gut microbiome that can be grown on a medium different than that for Bacteroides) from ceftriaxone, four highly cephalosporin-resistan...

Production of extended-spectrum β -lactamases and the potential indirect pathogenic role of Prevotella isolates from the cystic fibrosis respiratory microbiota

“…A recent study found that β-lactamase-producing Bacteroides spp. were able to shield a β-lactamase-negative E. coli isolate from the activity of ceftriaxone [29]. Likewise, we have shown that a β-lactamase-positive Prevotella isolate protected a susceptible P. aeruginosa isolate from the action of ceftazidime.…”

ACI‐1 beta‐lactamase is widespread across human gut microbiomes in Negativicutes due to transposons harboured by tailed prophages

“…First, Acidaminococcus and other Negativicutes have been found in clinical samples and may be involved in polymicrobial infections like abscesses (Jumas-Bilak et al, 2007;Tito et al, 2017), dysbiotic conditions like vaginosis (Zozaya-Hinchliffe et al, 2008), or complex disorders (Gough et al, 2015;Nam et al, 2018). Second, the secretion of betalactamases into the gut by commensal bacteria in response to beta-lactam antibiotics prescribed against bacterial pathogens could provide resistance for nearby bacteria, including pathogens, by collective resistance, sometimes termed indirect or passive resistance (Stiefel et al, 2015;Sorg et al, 2016).…”

Prediction of the intestinal resistome by a novel 3D-based method

“…Bacteroides or Prevotella species producing beta-lactamases that protected the microbiota when a beta-lactam was given 20,21,35,36 . Our results call for further experiments to identify protective species with ARDs of low human risk concern 27 that could potentially be included in synthetic microbiota as "bodyguards" for the bacteria of interest.…”