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New broad-spectrum antibiotics containing a pyrrolobenzodiazepine ring with activity against multidrug resistant Gram-negative bacteria.

Research output: Contribution to journalArticle

Pietro Picconi, Charlotte K. Hind, Kazi S. Nahar, Shirin Jamshidi, Lucia Di Maggio, Naima Saeed, Bonnie Evans, Jessica Solomons, Matthew E. Wand, J. Mark Sutton, Khondaker Miraz Rahman

Original languageEnglish
Pages (from-to)6941–6958
Number of pages18
JournalJournal of Medicinal Chemistry
Volume63
Issue number13
Early online date9 Jun 2020
DOIs
Publication statusPublished - 9 Jun 2020

King's Authors

Abstract

It is urgent to find new antibiotic classes with activity against multidrug resistant (MDR) Gram-negative pathogens as the pipeline of antibiotics is essentially empty. Modified pyrrolobenzodiazepines (PBDs) with a C8-linked aliphatic-heterocycle, provide a new class of broad-spectrum antibacterial agents with activity against multidrug resistant Gram-negative bacteria, including WHO priority pathogens. The structure-activity-relationship established that the third ring was particularly important for Gram-negative activity. Minimum inhibitory concentrations for the lead compounds ranged from 0.125 – 2 mg/L for MDR Gram-negative, excluding Pseudomonas aeruginosa, and between 0.03 - 1 mg/L for MDR Gram-positive species. The lead compounds were rapidly bactericidal with >5-log reduction in viable count within 4 hours for Acinetobacter baumannii and Klebsiella pneumoniae. The lead compound inhibited DNA gyrase in gel-based assays, with an IC50 of 3.16 +/- 1.36 mg/L. This study provides a new chemical scaffold for developing novel broad-spectrum antibiotics which can help replenish the pipeline of antibiotics.

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