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Enhanced Survival of Rifampin- and Streptomycin-Resistant Escherichia coli Inside Macrophages.

ABSTRACT: The evolution of multiple-antibiotic-resistant bacteria is an increasing global problem. Even though mutations causing resistance usually incur a fitness cost in the absence of antibiotics, the magnitude of such costs varies across environments and genomic backgrounds. We studied how the combination of mutations that confer resistance to rifampin (Rif(r)) and streptomycin (Str(r)) affects the fitness of Escherichia coli when it interacts with cells from the immune system, i.e., macrophages (M?s). We found that 13 Rif(r) Str(r) doubly resistant genotypes, of the 16 tested, show a survival advantage inside M?s, indicating that double resistance can be highly beneficial in this environment. Our results suggest that there are multiple paths to acquire multiple-drug resistance in this context, i.e., if a clone carrying Rif(r) allele H526 or S531 acquires a second mutation conferring Str(r), the resulting double mutant has a high probability of showing increased survival inside M?s. On the other hand, we found two cases of sign epistasis between mutations, leading to a significant decrease in bacterial survival. Remarkably, infection of M?s with one of these combinations, K88R+H526Y, resulted in an altered pattern of gene expression in the infected M?s. This indicates that the fitness effects of resistance may depend on the pattern of gene expression of infected host cells. Notwithstanding the benefits of resistance found inside M?s, the Rif(r) Str(r) mutants have massive fitness costs when the bacteria divide outside M?s, indicating that the maintenance of double resistance may depend on the time spent within and outside phagocytic cells.

SUBMITTER: Durao P

PROVIDER: S-EPMC4914683 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Enhanced Survival of Rifampin- and Streptomycin-Resistant Escherichia coli Inside Macrophages.

Durão Paulo P Gülereşi Daniela D Proença João J Gordo Isabel I

Antimicrobial agents and chemotherapy 20160620 7

The evolution of multiple-antibiotic-resistant bacteria is an increasing global problem. Even though mutations causing resistance usually incur a fitness cost in the absence of antibiotics, the magnitude of such costs varies across environments and genomic backgrounds. We studied how the combination of mutations that confer resistance to rifampin (Rif(r)) and streptomycin (Str(r)) affects the fitness of Escherichia coli when it interacts with cells from the immune system, i.e., macrophages (Mϕs) ...[more]

PMID: 27161646

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Project description:UnlabelledTreatment with streptomycin enhances the growth of human commensal Escherichia coli isolates in the mouse intestine, suggesting that the resident microbial community (microbiota) can inhibit the growth of invading microbes, a phenomenon known as "colonization resistance." However, the precise mechanisms by which streptomycin treatment lowers colonization resistance remain obscure. Here we show that streptomycin treatment rendered mice more susceptible to the development of chemically induced colitis, raising the possibility that the antibiotic might lower colonization resistance by changing mucosal immune responses rather than by preventing microbe-microbe interactions. Investigation of the underlying mechanism revealed a mild inflammatory infiltrate in the cecal mucosa of streptomycin-treated mice, which was accompanied by elevated expression of Nos2, the gene that encodes inducible nitric oxide synthase. In turn, this inflammatory response enhanced the luminal growth of E. coli by nitrate respiration in a Nos2-dependent fashion. These data identify low-level intestinal inflammation as one of the factors responsible for the loss of resistance to E. coli colonization after streptomycin treatment.ImportanceOur intestine is host to a complex microbial community that confers benefits by educating the immune system and providing niche protection. Perturbation of intestinal communities by streptomycin treatment lowers "colonization resistance" through unknown mechanisms. Here we show that streptomycin increases the inflammatory tone of the intestinal mucosa, thereby making the bowel more susceptible to dextran sulfate sodium treatment and boosting the Nos2-dependent growth of commensal Escherichia coli by nitrate respiration. These data point to the generation of alternative electron acceptors as a by-product of the inflammatory host response as an important factor responsible for lowering resistance to colonization by facultative anaerobic bacteria such as E. coli.

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Dataset Information

Enhanced Survival of Rifampin- and Streptomycin-Resistant Escherichia coli Inside Macrophages.

Publications

Enhanced Survival of Rifampin- and Streptomycin-Resistant Escherichia coli Inside Macrophages.

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