Synthesis and Evaluation of <i>Pseudomonas aeruginosa</i> ATP Synthase Inhibitors

Ciprich, John F.; Buckhalt, Alexander J. E.; Carroll, Lane L.; Chen, David; DeFiglia, Steven A.; McConnell, Riley S.; Parmar, Dhruvi J.; Pistor, Olivia L.; Rao, Aliyah B.; Rubin, M. Lillian; Volk, Grace E.; Steed, Ryan; Wolfe, Amanda L.

doi:10.1021/acsomega.2c03127

Cited by 5 publications

(18 citation statements)

References 32 publications

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“…In previous work, we conducted an initial SAR study of quinolines derivatized at the C1 and C2 positions and their inhibition of PA ATP synthesis activity, and we found that bulky constituents at C1 and C2 and hydrogen bonding capability at C2 related to stronger inhibition. Based on those results, we generated additional quinoline derivatives that maintained (methyl sulfide) or increased (benzyl sulfide) hydrophobic bulk at C1 and introduced bulky constituents at C2.…”

Section: Discussionmentioning

confidence: 98%

“…Previously, we synthesized a series of C1 and C2 quinoline analogs in order to determine if ATP synthesis inhibition could be a useful antibiotic development target in PA . From this study, we found that 6 of the quinolines were able to inhibit ATP synthesis in PA vesicles, with compound 1 (Figure C), which has a methyl sulfide at C1 and a l -tyrosine methyl ester at C2, being among the most active of the compounds surveyed.…”

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confidence: 99%

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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: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

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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“…In addition, ATP synthase subunits have been reported as an antibacterial target in Pseudomonas aeruginosa and others. 48 , 49 In addition, a severe reduction in ATP synthesis in Enterococcus faecalis and E. faecium was observed when treated with terpenoids from Salvia tingitana . 50 Our findings suggest that JR or MA contain phyto-molecules that could target the production of ATP and thus impart effects on energy-dependent metabolic pathways in P. gingivalis .…”

Section: Discussionmentioning

confidence: 99%

“…The downregulation of ATP synthase subunits would suppress the normal energy-dependent metabolic processes and growth of P. gingivalis . In addition, ATP synthase subunits have been reported as an antibacterial target in Pseudomonas aeruginosa and others. , In addition, a severe reduction in ATP synthesis in Enterococcus faecalis and E. faecium was observed when treated with terpenoids from Salvia tingitana .…”

Section: Discussionmentioning

confidence: 99%

Proteomic Profiling Reveals Cytotoxic Mechanisms of Action and Adaptive Mechanisms of Resistance in Porphyromonas gingivalis: Treatment with Juglans regia and Melaleuca alternifolia

et al. 2023

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The increasing trend in the rise of antibiotic-resistant bacteria pushes research to discover new efficacious antibacterial agents from natural and synthetic sources. Porphyromonas gingivalis is a well-known bacterium commonly known for causing periodontal disease, and it is associated with the pathogenesis of life-changing systemic conditions such as Alzheimer’s. Proteomic research can be utilized to test new antibacterial drugs and understand the adaptive resistive mechanisms of bacteria; hence, it is important in the drug discovery process. The current study focuses on identifying the antibacterial effects of Juglans regia (JR) and Melaleuca alternifolia (MA) on P. gingivalis and uses proteomics to identify modes of action while exploring its adaptive mechanisms. JR and MA extracts were tested for antibacterial efficacy using the agar well diffusion assay. A proteomic study was conducted identifying upregulated and downregulated proteins compared to control by 2D-DIGE analysis, and proteins were identified using MADLI-TOF/MS. The bacterial inhibition for JR was 20.14 ± 0.2, and that for MA was 19.72 ± 0.5 mm. Out of 88 differentially expressed proteins, there were 17 common differentially expressed proteins: 10 were upregulated and 7 were downregulated in both treatments. Among the upregulated proteins were Arginine-tRNA ligase, ATP-dependent Clp protease proteolytic, and flavodoxins. In contrast, down-regulated proteins were ATP synthase subunit alpha and quinone, among others, which are known antibacterial targets. STRING analysis indicated a strong network of interactions between differentially expressed proteins, mainly involved in protein translation, post-translational modification, energy production, metabolic pathways, and protein repair and degradation. Both extracts were equi-efficacious at inhibiting P. gingivalis and displayed some overlapping proteomic profiles. However, the MR extract had a greater fold change in its profile than the JA extract. Downregulated proteins indicated similarity in the mode of action, and upregulated proteins appear to be related to adaptive mechanisms important in promoting repair, growth, survival, virulence, and resistance. Hence, both extracts may be useful in preventing P. gingivalis-associated conditions. Furthermore, our results may be helpful to researchers in identifying new antibiotics which may offset these mechanisms of resistance.

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“…Due to this complexity, synthetic success and compound characterization were limited and having discrete phases prevented students from being able to troubleshoot their designs when synthetic challenges occurred. Therefore, few compounds (<10) advanced as far as biological evaluation and only 2 compounds were able to be published . Additionally, since students proposed their own mini-structure–activity relationship (SAR) studies, even the compounds that were generated were not cohesive enough to draw conclusions.…”

Section: Unc Asheville Drug Discovery Project Laboratorymentioning

confidence: 99%

Generating Publishable Data from Course-Based Undergraduate Research Experiences in Chemistry

Wolfe

Steed

2023

J. Chem. Educ.

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Embedding Course-based Undergraduate Research Experiences (CUREs) into chemistry curricula has become a best practice due to the overwhelming evidence that these experiences deepen students' content comprehension, improve students' problemsolving skills, and increase retention within the major. For these reasons, faculty are often encouraged to develop CUREs for their courses, which typically take a substantial amount of effort and administrative/financial support. To justify these efforts, one of the most cited benefits of CURE development for faculty specifically is that they can pilot research projects and publish data produced during CUREs in scientific publications. However, there is less evidence in the literature that these benefits commonly occur. Based on direct upperlevel, interdisciplinary CURE development experience and a national survey of faculty across institution types, it is clear that translating CURE data into publishable science is quite challenging due to several common barriers. Barriers identified include the need for follow up data that must be generated by either the faculty or a research student, the lack of reproducibility of data generated by novice students, and the lack of faculty time to write the manuscripts. Additionally, institution type (private vs public non-PhD granting; non-PhD granting vs PhD granting), faculty rank, and CURE level (lower vs upper-level courses), among other factors, impacted the likelihood of publication of CURE data. Based on these results and experiences, best practices for maximizing positive outcomes for both students and faculty with regard to CURE design and implementation have been developed.

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Synthesis and Evaluation of Pseudomonas aeruginosa ATP Synthase Inhibitors

Cited by 5 publications

References 32 publications

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

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

Proteomic Profiling Reveals Cytotoxic Mechanisms of Action and Adaptive Mechanisms of Resistance in Porphyromonas gingivalis: Treatment with Juglans regia and Melaleuca alternifolia

Generating Publishable Data from Course-Based Undergraduate Research Experiences in Chemistry

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