Antibiotics that Kill Gram-negative Bacteria by Restructuring the Outer Membrane Protein BamA
Modaresi, S. M.; Sugiyama, R.; Tram, N. D. T.; Jakob, R. P.; Phan, C.-S.; Saei, A. A.; Morishita, Y.; Muehlethaler, T.; Lim, J.; Ritz, D.; Long, P. S. Y.; Lehner, P. A.; Lim, Z. H.; Degen, M.; Yao, Z.; Maier, T.; Hou, Y.; Lee, J. Y.; Xu, J.; Yeat, A. Y. J.; Koh, K. T. S.; Goh, W. Y.; Ling, S. Y. H.; Chua, P. W. L.; Yamazaki, M.; Ee, P. L. R.; Hiller, S.; Morinaka, B. I.
Show abstract
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 {beta}-strand between {beta}1 and {beta}16 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.
Matching journals
The top 2 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Cell-free biosynthesis combined with deep learning accelerates de novo-development of antimicrobial peptides 97%
- Dynamic microfluidic single-cell screening identifies pheno-tuning compounds to potentiate tuberculosis therapy 97%
- Engineering of a fluorescent chemogenetic reporter with tunable color for advanced live-cell imaging 96%
Similar papers in this journal
Similar papers in this journal
- SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species 96%
- Mobile barrier mechanisms for Na+-coupled symport in an MFS sugar transporter 96%
- Structure-Function analysis of Lactiplantibacillus plantarum DltE reveals D-alanylated lipoteichoic acids as direct symbiotic cues supporting Drosophila juvenile growth 96%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.