Ritz, E.; Rossel, T.; Jacquier, N.

Antibiotic resistance is a growing public health concern. In this context, there is an urgent need of alternative antimicrobial agents effective towards multidrug-resistant bacteria. Antimicrobial peptides (AMPs) are naturally occurring peptides, part of the first antimicrobial line of defence of a wide variety of organisms. AMPs were identified as a promising alternative to classical antibiotics with a low potential of resistance emergence towards them. However, increasing pieces of evidence indicate that resistance to AMPs may be more common than expected. TAT-RasGAP317-326> is a semi-synthetic peptide first developed as an anticancer agent and later identified as an antibacterial agent. This peptide has a potent activity against Gram-negative bacteria, with a particularly low MIC (8 ug/ml) against Acinetobacter baumannii. While attempting to decipher the mode of action of TAT-RasGAP317-326, we performed in vitro resistance selection on Escherichia coli and only detected specific resistance to TAT-RasGAP317-326, without emergence of cross-resistance to other antimicrobial agents. In this study, we performed a similar in vitro resistance selection assay using several A. baumannii strains. We repeatedly observed, upon selection with TAT-RasGAP317-326, the emergence of cross-resistance to polymyxins, a family of polypeptidic antibiotics used as last resort agents towards multiresistant bacteria. A majority of the cross-resistant strains we selected had mutations in the pmrAB operon. Importantly, some of these mutations were identical to mutations detected in polymyxins resistant clinical isolates. Such mutations are known to cause resistance to polymyxins through modifications of the charge and structure of lipopolysaccharides at the bacterial surface. We thus show here that contact of A. baumannii with a semi-synthetic peptide structurally very different from polymyxins can induce the emergence of cross-resistance towards them. This indicates that caution should be taken with the clinical use of AMPs, since unexpected cross-resistance could emerge.