Mechanistic insight into the repair of C8-linked pyrrolobenzodiazepine monomer-mediated DNA damage. Issue 12 (28th October 2022)

• Record Type: Journal Article
• Authors: Joseph, Asha Mary; Nahar, Kazi; Daw, Saheli; Hasan, Md. Mahbub; Lo, Rebecca; Le, Tung B. K.; Rahman, Khondaker Miraz; Badrinarayanan, Anjana
• Is Part Of: RSC medicinal chemistry. Volume 13:Issue 12(2022)
• Page Start: 1621
• Page End: 1633
• Publication Date: 2022-10-28
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1039/d2md00194b
• Languages: English
• ISSNs: 2632-8682

Abstract

Abstract : Our understanding about the mode of action of pyrrolobenzodiazepine (PBD) monomers remains incomplete. This study reveals the DNA damaging potential of PBD monomers in bacteria, and identifies mechanisms involved in repair of these PBD-adducts. Abstract : Pyrrolobenzodiazepines (PBDs) are naturally occurring DNA binding compounds that possess anti-tumor and anti-bacterial activity. Chemical modifications of PBDs can result in improved DNA binding, sequence specificity and enhanced efficacy. More recently, synthetic PBD monomers have shown promise as payloads for antibody drug conjugates and anti-bacterial agents. The precise mechanism of action of these PBD monomers and their role in causing DNA damage remains to be elucidated. Here we characterized the damage-inducing potential of two C8-linked PBD bi-aryl monomers in Caulobacter crescentus and investigated the strategies employed by cells to repair the same. We show that these compounds cause DNA damage and efficiently kill bacteria, in a manner comparable to the extensively used DNA cross-linking agent mitomycin-C (MMC). However, in stark contrast to MMC which employs a mutagenic lesion tolerance pathway, we implicate essential functions for error-free mechanisms in repairing PBD monomer-mediated damage. We find that survival is severely compromised in cells lacking nucleotide excision repair and to a lesser extent, in cells with impaired recombination-based repair. Loss of nucleotide excision repair leads to significant increase in double-strand breaks, underscoring the critical role of this pathway in mediating repair of PBD-induced DNA lesions. Together, our study provides comprehensive insights into how mono-alkylating DNA-targeting therapeutic compounds like PBD monomers challenge cell growth, and identifies the specific mechanisms employed by the cell to counter the same.