Effects of in vivo Emergent Tigecycline Resistance on the Pathogenic Potential of Acinetobacter baumannii

Abstract

Multidrug-resistant lineages of Acinetobacter baumannii (MDRAB) are important nosocomial pathogens. As tigecycline remains active against most MDRAB we sought to investigate whether tigecycline resistance impacts biological fitness. The effects of treatment-emergent tigecycline resistance were investigated in vitro and in vivo using two pre- (AB210; W6976) and post-therapy (AB211; W7282) clinical pairs, recovered from individual patients, where tigecycline resistance was associated with up-regulated efflux activity. All isolates belonged to the same epidemic UK lineage. Significant differences were observed in end-point survival proportions between AB210 and AB211, but not between W6976 and W7282, using the Galleria mellonella infection model. Isolate AB211 outcompeted AB210 in vivo, in contrast to isolate W7282, which was outcompeted by its pre-therapy counterpart, W6972. Whole-genome sequencing of isolates W6976 and W7282 revealed a mutation in the adeABC regulatory gene, adeS in W7282; resulting in a Ser-8 → Arg substitution. Previous whole-genome comparison of AB210 and AB211 also identified a non-synonymous mutation in adeS, among several other lesions in genes involved in biofilm formation and DNA mismatch repair; consistent with the phenotypic differences described here. In conclusion, the differing effects on the wider phenotype were not predictable from the antibiograms or clonal lineage, despite a common mechanism of tigecycline resistance.