The DNA binding properties of 9-aminoacridine carboxamide Pt complexes

Kava, Hieronimus W.; Leung, Wai Y.; Galea, Anne M.; Murray, Vincent

doi:10.1016/j.bmc.2021.116191

Cited by 7 publications

(2 citation statements)

References 39 publications

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“…9-aminoacridine is currently used as an externally applied antiseptic, however its use as an antineoplastic agent has recently been proposed due to its action on PI3K [ 39 ]. Interestingly, 9-aminoacridine has also been used to derivatize cisplatin for improved DNA damaging capabilities [ 40 ]. It is therefore possible that 9-aminoacridine functions with cisplatin to severely damage the DNA, which overwhelms NER.…”

Section: Discussionmentioning

confidence: 99%

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

Bernacchia,

Gupta,

Paris

et al. 2023

PLoS Pathog

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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.

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Section: Discussionmentioning

confidence: 99%

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

Bernacchia,

Gupta,

Paris

et al. 2023

PLoS Pathog

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“…9-aminoacridine is used as an externally applied antiseptic, however its use as an antineoplastic agent has recently been proposed due to its action on PI3K (36) . Interestingly, 9-aminoacridine has also been used to derivatize cisplatin for improved DNA damaging capabilities (37). It is therefore possible that 9-aminoacridine functions with cisplatin to severely damage the DNA, which overwhelms NER.…”

Section: Discussionmentioning

confidence: 99%

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

Bernacchia

Gupta

Paris

et al. 2023

Preprint

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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.

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