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

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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
Issue number13
Early online date9 Jun 2020
Accepted/In press9 Jun 2020
E-pub ahead of print9 Jun 2020
Published9 Jul 2020


King's Authors


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.

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