Bernacchia, L. | bioRxiv Science

bioRxiv2023

Combining cancer chemotherapeutics with bacterial DNA repair inhibitors to develop novel antimicrobials

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. Here we have exploited the cytotoxicity of the anti-cancer compound cisplatin to screen for FDA-approved drugs that impair bacterial nucleotide excision DNA repair (NER), the primary mechanism bacteria use to repair cisplatin lesions. Five compounds have emerged of which three possess ideal antimicrobial properties including cell penetrance, specific activity for NER, and the ability to kill a multi-drug resistant clinically relevant E. coli strain. Targeting NER offers a new therapeutic approach for infections in cancer patients by combining antimicrobial activity with cancer chemotherapy.

biochemistry↗

bioRxiv2022

Culture media, DMSO and efflux affect the antibacterial activity of cisplatin and oxaliplatin

Cisplatin was originally discovered through its antibacterial action, and subsequently has found use as a potent broad spectrum anticancer agent. This study determines the effect of growth media and solvent on the antibacterial activity of cisplatin and its analogue, oxaliplatin. E. coli MG1655 or MG1655{Delta} tolC were treated with the platinum compounds under different conditions and susceptibility was determined. Our results showed that DMSO reduced the activity of cisplatin by 4-fold (MIC 12.5 mg/L) compared with 0.9% NaCl-solubilized cisplatin (MIC 3.12 mg/L) when tested in MOPS. Surprisingly, complete loss of activity was observed in Mueller Hinton Broth II (MHB II). By supplementing MOPS with individual components of MHB II such as the sulphur containing amino acids, L-cysteine and L-methionine, individually or in combination reduced activity by [≥]8-fold (MIC [≥]25 mg/L). Oxaliplatin was less active against E. coli (MIC 100 mg/L) but exhibited similar inactivation in the presence of DMSO, MHBII or MOPS spiked with L-cysteine and L-methionine (MIC [≥]400 mg/L). Our data suggest that the antibacterial activity of cisplatin and oxaliplatin is modulated by both choice of solvent and composition of growth media. We demonstrate that this is primarily due to sulphur-containing amino acids cysteine and methionine, an essential component of the recommended media for testing antimicrobial susceptibility, MHBII. Significance and impact of the studyAs well as an anticancer treatment, cisplatin possesses antibacterial activity and is active against AMR resistant persister cells, opening the possibility of renewed use against resistant bacterial strains. Our findings provide evidence on how the composition of growth media and choice of solvent modulate the antibacterial activity of cisplatin and its analogue, oxaliplatin. These observations provide a necessary, consistent standard for assessing the antibacterial activity of platinum-based compounds, as a precursor towards their application against bacterial infection. Graphical abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

microbiology↗