Alteration of adeS Contributes to Tigecycline Resistance and Collateral Sensitivity to Sulbactam in Acinetobacter baumannii

The treatment of extensively drug-resistant (XDR) A. baumannii has emerged as a major problem. Tigecycline (TGC) and sulbactam (SUL) are both effective antibiotics against XDR A. baumannii. Here, we investigated the in-host evolution and mechanism of collateral sensitivity (CS) phenomenon in development of tigecycline resistance accompanied by a concomitant increase of sulbactam susceptibility. A total of four XDR A. baumannii strains were sequentially isolated from the same patient suffering from bacteremia. Core-genome multilocus sequence typing separated all the strains into two clusters. Comparative analysis of isolate pair 1 revealed that multiplication of bla(OXA-23) within Tn2006 on the chromosome contributed to the change in the antimicrobial susceptibility phenotype of isolate pair 1. Additionally, we observed the emergence of CS to sulbactam in isolate pair 2, as demonstrated by an 8-fold increase in the TGC MIC with a simultaneous 4-fold decrease in the SUL MIC. Compared to the parental strain Ab-3557, YZM-0406 showed partial deletion in the two-component system sensor adeS. Reconstruction of the adeS mutant in Ab-3557 in situ suggested that TGC resistance and CS to SUL were mainly caused by the mutation of adeS. Overall, our study reported a novel CS combination of TGC and SUL in A. baumannii and further revealed a mechanism of CS attributed to the mutation of adeS. This study provides a valuable foundation for developing effective regimens and sequential combinations of tigecycline and sulbactam against XDR A. baumannii. IMPORTANCE Collateral sensitivity (CS) has become an increasingly common evolutionary trade-off during adaptive bacterial evolution. Here, we report a novel combination of tigecycline (TGC) resistance and CS to sulbactam (SUL) in A. baumannii. TGC and SUL are both effective antibiotics against XDR A. baumannii, and it is essential to reveal the mechanism of CS between TGC and SUL. In our study, the partial deletion of adeS, a two-component system sensor, was confirmed to be the key factor contributing to this CS phenomenon. This study provides a valuable foundation for developing effective regimens and sequential combinations of tigecycline and sulbactam against XDR A. baumannii.