Cross resistance emergence to polymyxins in Acinetobacter baumannii exposed in vitro to an antimicrobial peptide

Multidrug-resistant bacteria are a growing public health concern. Antimicrobial peptides (AMPs) are proposed alternatives to classical antibiotics towards infections caused by resistant bacteria. TAT-RasGAP_317-326 is an AMP able to target Gram-negative bacteria and is especially efficient towards Acinetobacter baumannii. In this study, we performed in vitro resistance selection on several A. baumannii strains, in order to determine to which extent these bacteria can develop resistance to TAT-RasGAP_317-326. A. baumannii rapidly developed resistance to TAT-RasGAP_317-326 and subsequently, in approximately half of the cases, cross-resistance to last-resort polypeptidic antibiotics polymyxins. Cross-resistant isolates predominantly bore mutations in the pmrAB operon, involved in modulation of lipopolysaccharides' charge at the bacterial surface, similarly to polymyxin-resistant clinical isolates. We thus show here that contact of A. baumannii with an AMP structurally different from polymyxins can induce unexpected cross-resistance towards them. This indicates that precautions must be taken for the clinical application of AMPs.