| Summary: | The cationic antimicrobial ß-hairpin, thanatin, was recently developed into drug-like analogues active against carbapenem-resistant Enterobacteriaceae (CRE). The analogues represent new antibiotics with a novel mode of action targeting LptA in the periplasm and disrupting LPS transport. The compounds lose antimicrobial efficacy when the sequence identity to <i>E. coli</i> LptA falls below 70%. We wanted to test the thanatin analogues against LptA of a phylogenetic distant organism and investigate the molecular determinants of inactivity. <i>Acinetobacter baumannii</i> (<i>A. baumannii</i>) is a critical Gram-negative pathogen that has gained increasing attention for its multi-drug resistance and hospital burden. <i>A. baumannii</i> LptA shares 28% sequence identity with <i>E. coli</i> LptA and displays an intrinsic resistance to thanatin and thanatin analogues (MIC values > 32 µg/mL) through a mechanism not yet described. We investigated the inactivity further and discovered that these CRE-optimized derivatives can bind to LptA of <i>A. baumannii</i> in vitro, despite the high MIC values. Herein, we present a high-resolution structure of <i>A. baumannii</i> LptAm in complex with a thanatin derivative <b>7</b> and binding affinities of selected thanatin derivatives. Together, these data offer structural insights into why thanatin derivatives are inactive against <i>A. baumannii</i> LptA, despite binding events in vitro.
|
|---|