Antibacterial Strategy Against : Inhibition of the Radical SAM Enzyme MqnE in Menaquinone Biosynthesis

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2019 Mar 21

PMID 30891141

Citations 4

Authors

Sumedh Joshi

Dmytro Fedoseyenko

Nilkamal Mahanta

Rodrigo G Ducati

Mu Feng

Vern L Schramm

Tadhg P Begley

Affiliations

Soon will be listed here.

Abstract

Aminofutalosine synthase (MqnE) catalyzes an important rearrangement reaction in menaquinone biosynthesis by the futalosine pathway. In this Letter, we report the identification of previously unreported inhibitors of MqnE using a mechanism-guided approach. The best inhibitor shows efficient inhibitory activity against (IC = 1.8 ± 0.4 μM) and identifies MqnE as a promising target for antibiotic development.

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References

Ducati R, Harijan R, Cameron S, Tyler P, Evans G, Schramm V . Transition-State Analogues of Campylobacter jejuni 5'-Methylthioadenosine Nucleosidase. ACS Chem Biol. 2018; 13(11):3173-3183. PMC: 6568325. DOI: 10.1021/acschembio.8b00781. View

Tanaka R, Kunisada T, Kushida N, Yamada K, Ikeda S, Noike M . Branched fatty acids inhibit the biosynthesis of menaquinone in Helicobacter pylori. J Antibiot (Tokyo). 2010; 64(1):151-3. DOI: 10.1038/ja.2010.133. View

Wang S, Haapalainen A, Yan F, Du Q, Tyler P, Evans G . A picomolar transition state analogue inhibitor of MTAN as a specific antibiotic for Helicobacter pylori. Biochemistry. 2012; 51(35):6892-4. PMC: 3437630. DOI: 10.1021/bi3009664. View

Ogasawara Y, Dairi T . Searching for potent and specific antibiotics against pathogenic Helicobacter and Campylobacter strains. J Ind Microbiol Biotechnol. 2018; 46(3-4):409-414. DOI: 10.1007/s10295-018-2108-3. View

Morrison J, WALSH C . The behavior and significance of slow-binding enzyme inhibitors. Adv Enzymol Relat Areas Mol Biol. 1988; 61:201-301. DOI: 10.1002/9780470123072.ch5. View

Evans G, Tyler P, Schramm V . Immucillins in Infectious Diseases. ACS Infect Dis. 2017; 4(2):107-117. PMC: 6034505. DOI: 10.1021/acsinfecdis.7b00172. View

Broderick J, Duffus B, Duschene K, Shepard E . Radical S-adenosylmethionine enzymes. Chem Rev. 2014; 114(8):4229-317. PMC: 4002137. DOI: 10.1021/cr4004709. View

Joshi S, Fedoseyenko D, Mahanta N, Manion H, Naseem S, Dairi T . Novel enzymology in futalosine-dependent menaquinone biosynthesis. Curr Opin Chem Biol. 2018; 47:134-141. DOI: 10.1016/j.cbpa.2018.09.015. View

Brenciaglia M, Fornara A, Scaltrito M, Braga P, Dubini F . Activity of amoxicillin, metronidazole, bismuth salicylate and six aminoglycosides against Helicobacter pylori. J Chemother. 1996; 8(1):52-4. DOI: 10.1179/joc.1996.8.1.52. View

10.

Chen D, Cunningham S, Cole N, Kohner P, Mandrekar J, Patel R . Phenotypic and Molecular Antimicrobial Susceptibility of Helicobacter pylori. Antimicrob Agents Chemother. 2017; 61(4. PMC: 5365656. DOI: 10.1128/AAC.02530-16. View

11.

Mahanta N, Fedoseyenko D, Dairi T, Begley T . Menaquinone biosynthesis: formation of aminofutalosine requires a unique radical SAM enzyme. J Am Chem Soc. 2013; 135(41):15318-21. PMC: 3855536. DOI: 10.1021/ja408594p. View

12.

Ogasawara Y, Kondo K, Ikeda A, Harada R, Dairi T . Identification of tirandamycins as specific inhibitors of the futalosine pathway. J Antibiot (Tokyo). 2017; 70(6):798-800. DOI: 10.1038/ja.2017.22. View

13.

Dowd P, Hershline R, Ham S, Naganathan S . Vitamin K and energy transduction: a base strength amplification mechanism. Science. 1995; 269(5231):1684-91. DOI: 10.1126/science.7569894. View

14.

Boersch M, Rudrawar S, Grant G, Zunk M . Menaquinone biosynthesis inhibition: a review of advancements toward a new antibiotic mechanism. RSC Adv. 2022; 8(10):5099-5105. PMC: 9078190. DOI: 10.1039/c7ra12950e. View

15.

Yamamoto T, Matsui H, Yamaji K, Takahashi T, Overby A, Nakamura M . Narrow-spectrum inhibitors targeting an alternative menaquinone biosynthetic pathway of Helicobacter pylori. J Infect Chemother. 2016; 22(9):587-92. DOI: 10.1016/j.jiac.2016.05.012. View

16.

Hin B, Majer P, Tsukamoto T . Facile synthesis of alpha-substituted acrylate esters. J Org Chem. 2002; 67(21):7365-8. DOI: 10.1021/jo026101s. View

17.

Dairi T . An alternative menaquinone biosynthetic pathway operating in microorganisms: an attractive target for drug discovery to pathogenic Helicobacter and Chlamydia strains. J Antibiot (Tokyo). 2009; 62(7):347-52. DOI: 10.1038/ja.2009.46. View

18.

Joshi S, Mahanta N, Fedoseyenko D, Williams H, Begley T . Aminofutalosine Synthase: Evidence for Captodative and Aryl Radical Intermediates Using β-Scission and S1 Trapping Reactions. J Am Chem Soc. 2017; 139(32):10952-10955. DOI: 10.1021/jacs.7b04209. View

19.

Matsui H, Takahashi T, Murayama S, Kawaguchi M, Matsuo K, Nakamura M . Protective efficacy of a hydroxy fatty acid against gastric Helicobacter infections. Helicobacter. 2017; 22(6). DOI: 10.1111/hel.12430. View

20.

Namanja-Magliano H, Evans G, Harijan R, Tyler P, Schramm V . Transition State Analogue Inhibitors of 5'-Deoxyadenosine/5'-Methylthioadenosine Nucleosidase from Mycobacterium tuberculosis. Biochemistry. 2017; 56(38):5090-5098. PMC: 6019266. DOI: 10.1021/acs.biochem.7b00576. View