| 1. |
- Chen, Huan, et al.
(författare)
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The mycobacterial membrane : a novel target space for anti-tubercular drugs
- 2018
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Ingår i: Frontiers in Microbiology. - : Frontiers Media S.A.. - 1664-302X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- uberculosis (TB) poses an enduring threat to global health. Consistently ranked among the top 10 causes of death worldwide since 2000, TB has now exceeded HIV-AIDS in terms of deaths inflicted by a single infectious agent. In spite of recently declining TB incident rates, these decreases have been incremental and fall short of threshold levels required to end the global TB epidemic. As in other infectious diseases, the emergence of resistant organisms poses a major impediment to effective TB control. Resistance in mycobacteria may evolve from genetic mutations in target genes which are transmitted during cell multiplication from mother cells to their progeny. A more insidious form of resistance involves sub-populations of non-growing (“dormant”) mycobacterial persisters. Quiescent and genetically identical to their susceptible counterparts, persisters exhibit non-inheritable drug tolerance. Their prevalence account for the protracted treatment period that is required for the treatment of TB. In order to improve the efficacy of treatment against mycobacterial persisters and drug-resistant organisms, novel antitubercular agents are urgently required. Selective targeting of bacterial membranes has been proposed as a viable therapeutic strategy against infectious diseases. The underpinning rationale is that a functionally intact cell membrane is vital for both replicating and dormant bacteria. Perturbing the membrane would thus disrupt a multitude of embedded targets with lethal pleiotropic consequences, besides limiting the emergence of resistant strains. There is growing interest in exploring small molecules as selective disruptors of the mycobacterial membrane. In this review, we examined the recent literature on different chemotypes with membrane perturbing properties, the mechanisms by which they induce membrane disruption and their potential as anti-TB agents. Cationic amphiphilicity is a signature motif that is required of membrane targeting agents but adherence to this broad physical requirement does not necessarily translate to conformity in terms of biological outcomes. Nor does it ensure selective targeting of mycobacterial membranes. These are unresolved issues that require further investigation.
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| 2. |
- Li, Ming, et al.
(författare)
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Indolylalkyltriphenylphosphonium analogues are membrane-depolarizing mycobactericidal agents
- 2017
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Ingår i: ACS Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 8:11, s. 1165-1170
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Tidskriftsartikel (refereegranskat)abstract
- Agents that selectively target the mycobacterial membrane could potentially shorten treatment time for tuberculosis, reduce relapse, and curtail emergence of resistant strains. The lipophilicity and extensive charge-delocalized state of the triphenylphosphonium cation strongly favor accumulation within bacterial membranes. Here, we explored the antimycobacterial activities and membrane-targeting properties of indolylalkyltriphenylphosphonium analogues. The most active analogues preferentially inhibited growth of Mycobacterium tuberculosis H37Rv (MIC50 2–4 μM) and were bactericidal against Mycobacterium bovis BCG (MBC99 3 μM). In spite of their propensity to accumulate within membranes, we found no evidence that these compounds permeabilized mycobacterial membranes or induced cell-envelope stress. Our investigations indicated that their bacterical effects stem from sustained depolarization of mycobacterial membranes and ensuing disruptive effects on electron transfer and cell division.
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| 3. |
- Li, Ming, et al.
(författare)
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Potency increase of spiroketal analogs of membrane inserting indolyl mannich base antimycobacterials is due to acquisition of MmpL3 inhibition
- 2020
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Ingår i: ACS - Infectious Diseases. - : American Chemical Society (ACS). - 2373-8227. ; 6:7, s. 1882-1893
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- Li, Ming, et al.
(författare)
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Resistance against membrane-inserting MmpL3 inhibitor through upregulation of MmpL5 in mycobacterium tuberculosis
- 2020
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Ingår i: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 64:12
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Tidskriftsartikel (refereegranskat)abstract
- Spiroketal indolyl Mannich bases (SIMBs) present a novel class of membrane-inserting antimycobacterials with efficacy in a tuberculosis mouse model. SIMBs exert their antibacterial activity by two mechanisms. The indolyl Mannich base scaffold causes permeabilization of bacteria, and the spiroketal moiety contributes to inhibition of the mycolic acid transporter MmpL3. Here, we show that low-level resistance to SIMBs arises by mutations in the transcriptional repressor MmpR5, resulting in upregulation of the efflux pump MmpL5.
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| 5. |
- Nyantakyi, Samuel A., et al.
(författare)
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Indolyl Azaspiroketal Mannich Bases Are Potent Antimycobacterial Agents with Selective Membrane Permeabilizing Effects and in Vivo Activity
- 2018
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 61:13, s. 5733-5750
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Tidskriftsartikel (refereegranskat)abstract
- The inclusion of an azaspiroketal Mannich base in the membrane targeting antitubercular 6-methoxy-l-n-octyl-lH-indole scaffold resulted in analogs with improved selectivity and submicromolar activity against Mycobacterium tuberculosis H37Rv. The potency enhancing properties of the spiro-fused ring motif was affirmed by SAR and validated in a mouse model of tuberculosis. As expected for membrane inserting agents, the indolyl azaspiroketal Mannich bases perturbed phospholipid vesicles, permeabilized bacterial cells, and induced the mycobacterial cell envelope stress reporter promoter piniBAC. Surprisingly, their membrane disruptive effects did not appear to be associated with bacterial membrane depolarization. This profile was not uniquely associated with azaspiroketal Mannich bases but was characteristic of indolyl Mannich bases as a class. Whereas resistant mycobacteria could not be isolated for a less potent indolyl Mannich base, the more potent azaspiroketal analog displayed low spontaneous resistance mutation frequency of 10-8/CFU. This may indicate involvement of an additional envelope-related target in its mechanism of action.
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