Antibiotics that Kill Gram-negative Bacteria by Restructuring the Outer Membrane Protein BamA

The essential outer membrane protein insertase BamA has recently emerged as a valid target for killing Gram-negative bacteria. Bamabactins, competitive inhibitors targeting the lateral gate of BamA, disrupt the substrate folding process, compromise the outer membrane integrity, and lead to bacterial cell death. Despite their promise, the full pharmacological potential of bamabactins remains underexploited. We applied phylogenetic genome mining and synthetic biology to identify xenorceptides which selectively kill Enterobacteriaceae . Mode of action studies show that xenorceptide A2 integrates itself into BamA as an additional β-strand between β1 and β16 at the lateral gate, inducing a conformation of BamA that has not been observed before. Biological evaluation of xenorceptide A2 shows promising activity in vitro and in vivo , and limited resistance which differentiates it from other bamabactin antibiotics. Our data show that the chemical diversity of bamabactins is far greater than previously recognized and thus an attractive source for antibiotic discovery.