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

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

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13 Citations (Scopus)
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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 with a C8-linked aliphatic heterocycle provide a new class of broad-spectrum antibacterial agents with activity against MDR 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 to 2 mg/L for MDR Gram-negative, excluding Pseudomonas aeruginosa, and between 0.03 and 1 mg/L for MDR Gram-positive species. The lead compounds were rapidly bactericidal with >5 log reduction in viable count within 4 h 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.

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 Jul 2020

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