Discovery of Bicyclic Inhibitors Against Menaquinone Biosynthesis

Choi, Seoung Ryoung; Larson, Marilynn A.; Hinrichs, Steven H.; Bartling, Amanda M.; Frandsen, Joel; Narayanasamy, Prabagaran

doi:10.4155/fmc.15.168

Cited by 30 publications

(33 citation statements)

References 17 publications

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“…16 Interestingly, not all of the enzymes have had signicant investigation into potential inhibitors. [18][19][20][21][22][23][24][25][26] To date the most promising results have come from inhibitors targeting the enzymes further downstream of the synthesis pathway. Major inhibitors that have been discovered to date will be reviewed in this article.…”

Section: Bacterial Synthesis Of Menaquinonementioning

confidence: 99%

Menaquinone biosynthesis inhibition: a review of advancements toward a new antibiotic mechanism

et al. 2018

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Section: Bacterial Synthesis Of Menaquinonementioning

confidence: 99%

Menaquinone biosynthesis inhibition: a review of advancements toward a new antibiotic mechanism

et al. 2018

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“…Thus, an urgent need exists for simplified, long-acting, and effective regimens to treat HIV and M. tuberculosis coinfection (5). …”

Section: Introductionmentioning

confidence: 99%

Ga(III) Nanoparticles Inhibit Growth of both Mycobacterium tuberculosis and HIV and Release of Interleukin-6 (IL-6) and IL-8 in Coinfected Macrophages

Choi

Britigan

Narayanasamy

2017

Antimicrob Agents Chemother

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Treatment of individuals coinfected with human immunodeficiency virus (HIV) type 1 and Mycobacterium tuberculosis is challenging due to the prolonged treatment requirements, drug toxicity, and emergence of drug resistance. Mononuclear phagocytes (MP; macrophages) are one of the natural reservoirs for both HIV and M. tuberculosis. Here, the treatment of HIV and M. tuberculosis coinfection was studied by preloading human macrophages with MP-targeted gallium (Ga) nanoparticles to limit subsequent simultaneous infection with both HIV and M. tuberculosis. Ga nanoparticles provided sustained drug release for 15 days and significantly inhibited the replication of both HIV and M. tuberculosis. Addition of Ga nanoparticles to MP already infected with M. tuberculosis or HIV resulted in a significant decrease in the magnitude of these infections, but the magnitude was less than that achieved with nanoparticle preloading of the MP. In addition, macrophages that were coinfected with HIV and M. tuberculosis and that were loaded with Ga nanoparticles reduced the levels of interleukin-6 (IL-6) and IL-8 secretion for up to 15 days after drug loading. Ga nanoparticles also reduced the levels of IL-6 and IL-8 secretion by ionomycin- and lipopolysaccharide-induced macrophages, likely by modulating the IκB kinase-β/NF-κB pathway. Delivery of Ga nanoparticles to macrophages is a potent long-acting approach for suppressing HIV and M. tuberculosis coinfection of macrophages in vitro and sets the stage for the development of new approaches to the treatment of these important infections.

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“…Previously, we reported that MenA inhibitors possessing a simple, chemical structural backbone of 7-methoxy naphthalene are highly active against Gram-positive bacteria with low micromolar MIC and IC 50 values (compound 1 and 2 in Fig. 2)6. Here, we synthesized novel compounds to explore structure-activity relationships (compounds 3 to 7 in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We previously reported that compound 1 and 2 exhibited inhibition of both M.tb and MenA enzyme activity with IC 50 values of 6 and 5 μg/mL, respectively6. We synthesized long chain compounds with different functionalities to improve activity.…”

Section: Resultsmentioning

confidence: 99%

“…Inhibitors of enzymes involved in MK biosynthesis demonstrate that targeting these enzymes may lead to therapeutics for treatments of infections by Gram-positive bacteria including Bacillus subtilis, M. tuberculosis , and S. aureus 67. 4-oxo-4-phenylbutanoate analogues were developed as MenB inhibitors active against MRSA and both replicating and nonreplicating M. tuberculosis 89.…”

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confidence: 99%

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Novel long-chain compounds with both immunomodulatory and MenA inhibitory activities against Staphylococcus aureus and its biofilm

Choi

Frandsen

Narayanasamy

2017

Sci Rep

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Menaquinone (MK) biosynthesis pathway is a potential target for evaluating antimicrobials in gram-positive bacteria. Here, 1,4-dihydroxy-2-naphthoate prenyltransferase (MenA) was targeted to reduce methicillin-resistant Staphylococcus aureus (MRSA) growth. MenA inhibiting, long chain-based compounds were designed, synthesized and evaluated against MRSA and menaquinone utilizing bacteria in aerobic conditions. The results showed that these bacteria were susceptible to most of the compounds. Menaquinone (MK-4) supplementation rescued MRSA growth, suggesting these compounds inhibit MK biosynthesis. 3a and 7c exhibited promising inhibitory activities with MICs ranging 1–8 μg/mL against MRSA strains. The compounds did not facilitate small colony variant formation. These compounds also inhibited the biofilm growth by MRSA at high concentration. Compounds 3a, 6b and 7c displayed a promising extracellular bactericidal activity against MRSA at concentrations equal to and four-fold less than their respective MICs. We also observed cytokines released from THP-1 macrophages treated with compounds 3a, 6b and 7c and found decreases in TNF-α and IL-6 release and increase in IL-1β. These data provide evidence that MenA inhibitors act as TNF-α and IL-6 inhibitors, raising the potential for development and application of these compounds as potential immunomodulatory agents.

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Discovery of Bicyclic Inhibitors Against Menaquinone Biosynthesis

Cited by 30 publications

References 17 publications

Menaquinone biosynthesis inhibition: a review of advancements toward a new antibiotic mechanism

Menaquinone biosynthesis inhibition: a review of advancements toward a new antibiotic mechanism

Ga(III) Nanoparticles Inhibit Growth of both Mycobacterium tuberculosis and HIV and Release of Interleukin-6 (IL-6) and IL-8 in Coinfected Macrophages

Novel long-chain compounds with both immunomodulatory and MenA inhibitory activities against Staphylococcus aureus and its biofilm

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