Adaptation of a bacterial multidrug resistance system revealed by the structure and function of AlbA

Sikandar, A., Cirnski, K., Testolin, G., Volz, C., Brönstrup, M., Kalinina, O. V., Müller, R. and Koehnke, J. (2018) Adaptation of a bacterial multidrug resistance system revealed by the structure and function of AlbA. Journal of the American Chemical Society, 140(48), pp. 16641-16649. (doi: 10.1021/jacs.8b08895) (PMID:30422653)

Abstract

To combat the rise of antimicrobial resistance, the discovery of new antibiotics is paramount. Albicidin and cystobactamid are related natural product antibiotics with potent activity against Gram-positive and, crucially, Gram-negative pathogens. AlbA has been reported to neutralize albicidin by binding it with nanomolar affinity. To understand this potential resistance mechanism, we determined structures of AlbA and its complex with albicidin. The structures revealed AlbA to be comprised of two domains, each unexpectedly resembling the multiantibiotic neutralizing protein TipA. Binding of the long albicidin molecule was shared pseudosymmetrically between the two domains. The structure also revealed an unexpected chemical modification of albicidin, which we demonstrate to be promoted by AlbA, and to reduce albicidin potency; we propose a mechanism for this reaction. Overall, our findings suggest that AlbA arose through internal duplication in an ancient TipA-like gene, leading to a new binding scaffold adapted to the sequestration of long-chain antibiotics.

• Item Type: Articles
• Additional Information: J.K. acknowledges the DFG for an Emmy-Noether Fellowship (KO 4116/3-1).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Koehnke, Professor Jesko
• Authors: Sikandar, A., Cirnski, K., Testolin, G., Volz, C., Brönstrup, M., Kalinina, O. V., Müller, R., and Koehnke, J.
• College/School: College of Science and Engineering > School of Chemistry
• Journal Name: Journal of the American Chemical Society
• Publisher: American Chemical Society
• ISSN: 0002-7863
• ISSN (Online): 1520-5126
• Published Online: 13 November 2018
• Copyright Holders: Copyright © 2018 American Chemical Society
• First Published: First published in Journal of the American Chemical Society 140(48):16641-16649
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher