Developing novel antimicrobials by combining cancer chemotherapeutics with bacterial DNA repair inhibitors

• Published in: PLoS pathogens Vol. 19; no. 12; p. e1011875
• Main Authors: Bernacchia, Lorenzo, Gupta, Arya, Paris, Antoine, Moores, Alexandra A, Kad, Neil M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-12-2023; Public Library of Science (PLoS)
• Subjects: Anti-Infective Agents; Antimicrobial agents; Antimitotic agents; Antineoplastic agents; Antineoplastic drugs; Apoptosis; Bacteria; Bacterial genetics; Bacterial infections; Biology and life sciences; Cancer; Cancer therapies; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Cisplatin - therapeutic use; Deoxyribonucleic acid; DNA; DNA Damage; DNA Repair; DNA replication; DNA, Bacterial; Drug approval; Drug dosages; Drug resistance; Drugs; E coli; Enzymes; Escherichia coli; Escherichia coli - genetics; FDA approval; Genetic aspects; Health aspects; Humans; Immune system; Immunosuppressive agents; Infection; Medicine and Health Sciences; Morbidity; Mortality; Multidrug resistance; Neoplasms - drug therapy; Neutropenia; Nosocomial infections; Nucleotides; Pathogens; Patient outcomes; Pixantrone; Prevention; Research and Analysis Methods; United Kingdom; United Kingdom
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1011875

Cancer chemotherapeutics kill rapidly dividing cells, which includes cells of the immune system. The resulting neutropenia predisposes patients to infection, which delays treatment and is a major cause of morbidity and mortality. To tackle this problem, we have isolated several compounds that inhibit bacterial DNA repair, alone they are non-toxic, however in combination with DNA damaging anti-cancer drugs, they prevent bacterial growth. These compounds were identified through screening of an FDA-approved drug library in the presence of the anti-cancer compound cisplatin. Using a series of triage tests, the screen was reduced to a handful of drugs that were tested for specific activity against bacterial nucleotide excision DNA repair (NER). Five compounds emerged, of which three possess promising antimicrobial properties including cell penetrance, and the ability to block replication in a multi-drug resistant clinically relevant E. coli strain. This study suggests that targeting NER could offer a new therapeutic approach tailor-made for infections in cancer patients, by combining cancer chemotherapy with an adjuvant that targets DNA repair.