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Potency increase of...
Potency increase of spiroketal analogs of membrane inserting indolyl mannich base antimycobacterials is due to acquisition of MmpL3 inhibition
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- Li, Ming (author)
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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- Phua, Zheng Yen (author)
- Department of Chemistry, Faculty of Science, National University of Singapore, Singapore
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- Xi, Yu (author)
- Department of Chemistry, Faculty of Science, National University of Singapore, 1Singapore
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- Xu, Zhujun (author)
- Department of Chemistry, Faculty of Science, National University of Singapore, Singapore
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- Nyantakyi, Samuel A. (author)
- Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore
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- Li, Wei (author)
- Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States
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- Jackson, Mary (author)
- Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States
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- Wong, Ming Wah (author)
- Department of Chemistry, Faculty of Science, National University of Singapore, Singapore
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- Lam, Yulin (author)
- Department of Chemistry, Faculty of Science, National University of Singapore, Singapore
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- Chng, Shu Sin (author)
- Department of Chemistry, Faculty of Science, National University of Singapore, 117543 Singapore;Singapore Centre for Environmental Life Science Engineering (SCELSE), National University of Singapore, Singapore
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- Go, Mei Lin (author)
- Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore
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- Dick, Thomas (author)
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 117545 Singapore;Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey 07110, United States;Department of Medical Sciences, Hackensack Meridian School of Medicine at Seton Hall University, Nutley, New Jersey, United States
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(creator_code:org_t)
- 2020-05-15
- 2020
- English.
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In: ACS - Infectious Diseases. - : American Chemical Society (ACS). - 2373-8227. ; 6:7, s. 1882-1893
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Abstract
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- Chemistry campaigns identified amphiphilic indolyl Mannich bases as novel membrane-permeabilizing antimycobacterials. Spiroketal analogs of this series showed increased potency, and the lead compound 1 displayed efficacy in a mouse model of tuberculosis. Yet the mechanism by which the spiroketal moiety accomplished the potency “jump” remained unknown. Consistent with its membrane-permeabilizing mechanism, no resistant mutants could be isolated against indolyl Mannich base 2 lacking the spiroketal moiety. In contrast, mutations resistant against spiroketal analog 1 were obtained in mycobacterial membrane protein large 3 (MmpL3), a proton motive force (PMF)-dependent mycolate transporter. Thus, we hypothesized that the potency jump observed for 1 may be due to MmpL3 inhibition acquired by the addition of the spiroketal moiety. Here we showed that 1 inhibited MmpL3 flippase activity without loss of the PMF, colocalized with MmpL3tb–GFP in intact organisms, and yielded a consistent docking pose within the “common inhibitor binding pocket” of MmpL3. The presence of the spiroketal motif in 1 ostensibly augmented its interaction with MmpL3, an outcome not observed in the nonspiroketal analog 2, which displayed no cross-resistance to mmpL3 mutants, dissipated the PMF, and docked poorly in the MmpL3 binding pocket. Surprisingly, 2 inhibited MmpL3 flippase activity, which may be an epiphenomenon arising from its wider membrane disruptive effects. Hence, we conclude that the potency increase associated with the spiroketal analog 1 is linked to the acquisition of a second mechanism, MmpL3 inhibition. In contrast, the nonspiroketal analog 2 acts pleiotropically, affecting several cell membrane-embedded targets, including MmpL3, through its membrane permeabilizing and depolarizing effects.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Mikrobiologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Microbiology in the medical area (hsv//eng)
Keyword
- Mycobacterium tuberculosi
- s MmpL3
- indolyl Mannich bases
- membrane permeabilization
- cell membrane
- cationic amphiphiles
Publication and Content Type
- ref (subject category)
- art (subject category)
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Li, Ming
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Phua, Zheng Yen
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Xi, Yu
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Xu, Zhujun
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Nyantakyi, Samue ...
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Li, Wei
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show more...
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Jackson, Mary
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Wong, Ming Wah
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Lam, Yulin
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Chng, Shu Sin
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Go, Mei Lin
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Dick, Thomas
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ACS - Infectious ...
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Umeå University