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Synergistic effects of antimicrobial peptides and antibiotics against Clostridium difficile.

ABSTRACT: Accelerating rates of health care-associated infections caused by Clostridium difficile, with increasing recurrence and rising antibiotic resistance rates, have become a serious problem in recent years. This study was conducted to explore whether a combination of antibiotics with human antimicrobial peptides may lead to an increase in antibacterial activity. The in vitro activities of the antimicrobial peptides HBD1 to HBD3, HNP1, HD5, and LL-37 and the antibiotics tigecycline, moxifloxacin, piperacillin-tazobactam, and meropenem alone or in combination against 10 toxinogenic and 10 nontoxinogenic C. difficile strains were investigated. Bacterial viability was determined by flow cytometry and toxin production by enzyme-linked immunosorbent assay (ELISA). When combined at subinhibitory concentrations, antimicrobial peptides and antibiotics generally led to an additive killing effect against toxinogenic and nontoxinogenic C. difficile strains. However, LL-37 and HBD3 acted in synergism with all the antibiotics that were tested. Electron microscopy revealed membrane perturbation in bacterial cell walls by HBD3. In 3 out of 10 toxinogenic strains, HBD3, LL-37, piperacillin-tazobactam, and meropenem administration led to an increased toxin release which was not neutralized by the addition of HNP1. Antimicrobial peptides increase the bacterial killing of antibiotics against C. difficile regardless of the antibiotics' mode of action. Membrane perturbation in or pore formation on the bacterial cell wall may enhance the uptake of antibiotics and increase their antibacterial effect. Therefore, a combination of antibiotics with antimicrobial peptides may represent a promising novel approach to the treatment of C. difficile infections.

SUBMITTER: Nuding S

PROVIDER: S-EPMC4187972 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Probiotics might offer an attractive alternative to prevent and control Clostridium difficile (C. difficile) infection (CDI). Limited information is available on the ability of commercially used bifidobacterial strains to inhibit C. difficile. This study examined the anti-clostridial effects of Bifidobacterium longum JDM301, a widely used commercial probiotic strain in China, in vitro and in vivo. In vitro evaluation revealed a significant reduction in C. difficile counts when JDM301 was co-cultured with C. difficile, which was correlated with the significant decrease in clostridial toxin titres (TcdA and TcdB). Furthermore, the cell-free culture supernatants (CFS) of JDM301 inhibited C. difficile growth and degraded TcdA and TcdB. Notably, the results showed that acid pH promoted the degradation of TcdA by CFS from JDM301. Furthermore, comparative studies among 10 B. longum strains were performed, which showed that the inhibitory effect of CFS from JDM301 was similar with the other 8 B. longum strains and higher than strain BLY1. However, when it was neutralized, the significant different was lost. When present together, it was suggested that the acid pH induced by probiotics not only played important roles in the growth inhibition against C. difficile resulting in the reduction of toxins titres, but also directly promoted the degradation of clostridial toxin. In vivo studies proved that JDM301 partially relieved damage to tissues caused by C. difficile and also decreased the number of C. difficile and toxin levels. In summary, our results demonstrated that the commercial strain, JDM301 could be considered a probiotic able to exert anti-toxin capability and most of the CFS from Bifidobacterium were able to inhibit the growth of C. difficile, depending on acid pH. These results highlighted a potential that JDM301 could be helpful in preventing CDI and that most of the bifidobacterial strains could (at least partially) exert protective effects by reducing toxin titres through growth inhibition against toxigenic C. difficile.

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Synergistic effects of antimicrobial peptides and antibiotics against Clostridium difficile.

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