Complex Effects of Macrolide Venturicidins on Bacterial F-ATPases Likely Contribute to Their Action as Antibiotic Adjuvants

Milgrom, Yakov M.; Duncan, T. M.

doi:10.21203/rs.3.rs-448117/v1

Cited by 1 publication

(1 citation statement)

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“…This assay tests the reverse activity of ATP synthase, which uses ATP hydrolysis to pump H + into the lumen of the vesicle, where decreased interior pH quenches a fluorescent dye. PA vesicles have low activity relative to E. coli (DK8/pFV2), a phenotype observed previously in PA 15 and shared by the closely related ATP synthase from A. baumannii. 17 Consistent with the behavior of PA vesicles, vesicles prepared from DK8/pASH20 also showed reduced H + -pumping activity relative to DK8/pFV2.…”

Section: ■ Results and Discussionmentioning

confidence: 51%

Quinoline Compounds Targeting the c-Ring of ATP Synthase Inhibit Drug-Resistant Pseudomonas aeruginosa

Fraunfelter,

Pugh,

Williams

et al. 2023

ACS Infect. Dis.

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Pseudomonas aeruginosa (PA) is a Gram-negative, biofilm-forming bacterium and an opportunistic pathogen. The growing drug resistance of PA is a serious threat that necessitates the discovery of novel antibiotics, ideally with previously underexplored mechanisms of action. Due to their central role in cell metabolism, bacterial bioenergetic processes are of increasing interest as drug targets, especially with the success of the ATP synthase inhibitor bedaquiline to treat drug-resistant tuberculosis. Like Mycobacterium tuberculosis, PA requires F1Fo ATP synthase for growth, even under anaerobic conditions, making the PA ATP synthase an ideal drug target for the treatment of drug-resistant infection. In previous work, we conducted an initial screen for quinoline compounds that inhibit ATP synthesis activity in PA. In the present study, we report additional quinoline derivatives, including one with increased potency against PA ATP synthase in vitro and antibacterial activity against drug-resistant PA. Moreover, by expressing the PA ATP synthase in Escherichia coli, we show that mutations in the H+ binding site on the membrane-embedded rotor ring alter inhibition by the reported quinoline compounds. Identification of a potent inhibitor and its probable binding site on ATP synthase enables further development of promising quinoline derivatives into a viable treatment for drug-resistant PA infection.

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Section: ■ Results and Discussionmentioning

confidence: 51%