A Chemical-Intervention Strategy to Circumvent Peptide Hydrolysis by D-Stereoselective Peptidases

Samantha Bann; Ross Ballantine; Yong-Xin Li; Pei-Yuan Qian; Stephen Cochrane

doi:10.1021/acs.jmedchem.9b01078

A Chemical-Intervention Strategy to Circumvent Peptide Hydrolysis by D-Stereoselective Peptidases

Samantha Bann, Ross Ballantine, Yong-Xin Li, Pei-Yuan Qian, Stephen Cochrane

School of Chemistry and Chemical Engineering

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Abstract

D-Stereoselective peptidases that degrade non-ribosomal peptides (NRPs) were recently discovered and could have serious implications for the future of NRPs as antibiotics. Herein, we report chemical modifications that can be used to impart re-sistance to the D-peptidases BogQ and TriF. New tridecaptin A analogues were synthesized that retain strong antimicrobial activity and have significantly enhanced D-peptidase stability. In vitro assays confirmed that synthetic analogues retain the ability to bind to their cellular receptor, peptidoglycan intermediate lipid II.

Original language	English
Pages (from-to)	10466-10472
Journal	Journal of Medicinal Chemistry
Volume	62
Issue number	22
DOIs	https://doi.org/10.1021/acs.jmedchem.9b01078
Publication status	Published - 27 Nov 2019

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Bann, S., Ballantine, R., Li, Y-X., Qian, P-Y., & Cochrane, S. (2019). A Chemical-Intervention Strategy to Circumvent Peptide Hydrolysis by D-Stereoselective Peptidases. Journal of Medicinal Chemistry, 62(22), 10466-10472. https://doi.org/10.1021/acs.jmedchem.9b01078

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AB - D-Stereoselective peptidases that degrade non-ribosomal peptides (NRPs) were recently discovered and could have serious implications for the future of NRPs as antibiotics. Herein, we report chemical modifications that can be used to impart re-sistance to the D-peptidases BogQ and TriF. New tridecaptin A analogues were synthesized that retain strong antimicrobial activity and have significantly enhanced D-peptidase stability. In vitro assays confirmed that synthetic analogues retain the ability to bind to their cellular receptor, peptidoglycan intermediate lipid II.

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10.1021/acs.jmedchem.9b01078Licence: CC BY

A Chemical-Intervention Strategy To Circumvent Peptide Hydrolysis by d-Stereoselective Peptidases
Copyright 2019 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 909 KBLicence: CC BY