Inhibitory Compounds Targeting Plasmodium falciparum Gyrase B

Pakosz, Zuzanna; Lin, Ting-Yu; Michalczyk, Elizabeth; Nagano, Soshichiro; Heddle, Jonathan Gardiner

Abstract

Malaria persists as a major health problem due to the spread of drug resistance and the lack of effective vaccines. DNA gyrase is a well-validated and extremely effective therapeutic target in bacteria, and it is also known to be present in the apicoplast of malarial species, including Plasmodium falciparum. This raises the possibility that it could be a useful target for novel antimalarials. To date, characterization and screening of this gyrase have been hampered by difficulties in cloning and purification of the GyrA subunit, which is necessary together with GyrB for reconstitution of the holoenzyme. To overcome this, we employed a library of compounds with specificity for P. falciparum GyrB and assessed them in activity tests utilizing P. falciparum GyrB together with Escherichia coli GyrA to reconstitute a functional hybrid enzyme. Two inhibitory compounds were identified that preferentially inhibited the supercoiling activity of the hybrid enzyme over the E. coli enzyme. Of these, purpurogallin (PPG) was found to disrupt DNA binding to the hybrid gyrase complex and thus reduce the DNA-induced ATP hydrolysis of the enzyme. Binding studies indicated that PPG showed higher-affinity binding to P. falciparum GyrB than to the E. coli protein. We suggest that PPG achieves its inhibitory effect on gyrase through interaction with P. falciparum GyrB leading to disruption of DNA binding and, consequently, reduction of DNA-induced ATPase activity. The compound also showed an inhibitory effect against the malaria parasite in vitro and may be of interest for further development as an antimalarial agent.

Citation

Pakosz, Z., Lin, T., Michalczyk, E., Nagano, S., & Heddle, J. G. (2021). Inhibitory Compounds Targeting Plasmodium falciparum Gyrase B. Antimicrobial Agents and Chemotherapy, 65(10), https://doi.org/10.1128/aac.00267-21

• Journal Article Type: Article
• Acceptance Date: Jul 26, 2021
• Online Publication Date: Sep 17, 2021
• Publication Date: Sep 17, 2021
• Deposit Date: Nov 2, 2023
• Journal: Antimicrobial Agents and Chemotherapy
• Print ISSN: 0066-4804
• Electronic ISSN: 1098-6596
• Publisher: American Society for Microbiology
• Peer Reviewed: Peer Reviewed
• Volume: 65
• Issue: 10
• DOI: https://doi.org/10.1128/aac.00267-21
• Keywords: Infectious Diseases; Pharmacology (medical); Pharmacology
• Public URL: https://durham-repository.worktribe.com/output/1875177
• Additional Information: This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).