DC-159a Shows Inhibitory Activity Against DNA Gyrases of Mycobacterium Leprae

Overview

Journal PLoS Negl Trop Dis

Specialties Infectious Diseases
Tropical Medicine

Date 2016 Sep 30

PMID 27681932

Citations 4

Authors

Tomoyuki Yamaguchi

Kazumasa Yokoyama

Chie Nakajima

Yasuhiko Suzuki

Affiliations

Soon will be listed here.

Abstract

Background: Fluoroquinolones are a class of antibacterial agents used for leprosy treatment. Some new fluoroquinolones have been attracting interest due to their remarkable potency that is reportedly better than that of ofloxacin, the fluoroquinolone currently recommended for treatment of leprosy. For example, DC-159a, a recently developed 8-methoxy fluoroquinolone, has been found to be highly potent against various bacterial species. Nonetheless, the efficacy of DC-159a against Mycobacterium leprae is yet to be examined.

Methodology/principal Findings: To gather data that can support highly effective fluoroquinolones as candidates for new remedies for leprosy treatment, we conducted in vitro assays to assess and compare the inhibitory activities of DC-159a and two fluoroquinolones that are already known to be more effective against M. leprae than ofloxacin. The fluoroquinolone-inhibited DNA supercoiling assay using recombinant DNA gyrases of wild type and ofloxacin-resistant M. leprae revealed that inhibitory activities of DC-159a and sitafloxacin were at most 9.8- and 11.9-fold higher than moxifloxacin. Also the fluoroquinolone-mediated cleavage assay showed that potencies of those drugs were at most 13.5- and 9.8-fold higher than moxifloxacin. In addition, these two drugs retained their inhibitory activities even against DNA gyrases of ofloxacin-resistant M. leprae.

Conclusions/significance: The results indicated that DC-159a and sitafloxacin are more effective against wild type and mutant M. leprae DNA gyrases than moxifloxacin, suggesting that these antibacterial drugs can be good candidates that may supersede current fluoroquinolone remedies. DC-159a in particular is very promising because it is classified in a subgroup of fluoroquinolones that is known to be less likely to cause adverse effects. Our results implied that DC-159a is well worth further investigation to ascertain its in vivo effectiveness and clinical safety for humans.

Citing Articles

In vitro and ex vivo activity of the fluoroquinolone DC-159a against mycobacteria.

Imperiale B, Mancino M, Moyano R, de la Barrera S, Morcillo N J Antibiot (Tokyo). 2024; 77(5):306-314.

PMID: 38438500 DOI: 10.1038/s41429-024-00709-3.

Characterization of DNA Gyrase Activity and Elucidation of the Impact of Amino Acid Substitution in GyrA on Fluoroquinolone Resistance in Mycobacterium avium.

Thapa J, Chizimu J, Kitamura S, Akapelwa M, Suwanthada P, Miura N Microbiol Spectr. 2023; 11(3):e0508822.

PMID: 37067420 PMC: 10269562. DOI: 10.1128/spectrum.05088-22.

Structure-Guided Computational Approaches to Unravel Druggable Proteomic Landscape of .

Vedithi S, Malhotra S, Acebron-Garcia-de-Eulate M, Matusevicius M, Monteiro Torres P, Blundell T Front Mol Biosci. 2021; 8:663301.

PMID: 34026836 PMC: 8138464. DOI: 10.3389/fmolb.2021.663301.

Towards leprosy elimination by 2020: forecasts of epidemiological indicators of leprosy in Corrientes, a province of northeastern Argentina that is a pioneer in leprosy elimination.

Odriozola E, Quintana A, Gonzalez V, Pasetto R, Utges M, Bruzzone O Mem Inst Oswaldo Cruz. 2017; 112(6):419-427.

PMID: 28591402 PMC: 5446231. DOI: 10.1590/0074-02760160490.

References

Matsuoka M, Budiawan T, Aye K, Kyaw K, Tan E, Dela Cruz E . The frequency of drug resistance mutations in Mycobacterium leprae isolates in untreated and relapsed leprosy patients from Myanmar, Indonesia and the Philippines. Lepr Rev. 2008; 78(4):343-52. View

Consigny S, Bentoucha A, Bonnafous P, Grosset J, Ji B . Bactericidal activities of HMR 3647, moxifloxacin, and rifapentine against Mycobacterium leprae in mice. Antimicrob Agents Chemother. 2000; 44(10):2919-21. PMC: 90182. DOI: 10.1128/AAC.44.10.2919-2921.2000. View

Matsuoka M . The history of Mycobacterium leprae Thai-53 strain. Lepr Rev. 2010; 81(2):137. View

Williams D, Gillis T . Drug-resistant leprosy: monitoring and current status. Lepr Rev. 2013; 83(3):269-81. View

Pardillo F, Burgos J, Fajardo T, Dela Cruz E, Abalos R, Paredes R . Powerful bactericidal activity of moxifloxacin in human leprosy. Antimicrob Agents Chemother. 2008; 52(9):3113-7. PMC: 2533472. DOI: 10.1128/AAC.01162-07. View

Dhople A, Namba K . In vivo susceptibility of Mycobacterium leprae to sitafloxacin (DU-6859a), either singly or in combination with rifampicin analogues. Int J Antimicrob Agents. 2003; 21(3):251-5. DOI: 10.1016/s0924-8579(02)00351-5. View

Yokoyama K, Kim H, Mukai T, Matsuoka M, Nakajima C, Suzuki Y . Impact of amino acid substitutions in B subunit of DNA gyrase in Mycobacterium leprae on fluoroquinolone resistance. PLoS Negl Trop Dis. 2012; 6(10):e1838. PMC: 3469482. DOI: 10.1371/journal.pntd.0001838. View

Yokoyama K, Kim H, Mukai T, Matsuoka M, Nakajima C, Suzuki Y . Amino acid substitutions at position 95 in GyrA can add fluoroquinolone resistance to Mycobacterium leprae. Antimicrob Agents Chemother. 2011; 56(2):697-702. PMC: 3264231. DOI: 10.1128/AAC.05890-11. View

Champoux J . DNA topoisomerases: structure, function, and mechanism. Annu Rev Biochem. 2001; 70:369-413. DOI: 10.1146/annurev.biochem.70.1.369. View

10.

Marutani K, Matsumoto M, Otabe Y, Nagamuta M, Tanaka K, Miyoshi A . Reduced phototoxicity of a fluoroquinolone antibacterial agent with a methoxy group at the 8 position in mice irradiated with long-wavelength UV light. Antimicrob Agents Chemother. 1993; 37(10):2217-23. PMC: 192253. DOI: 10.1128/AAC.37.10.2217. View

11.

Turnidge J . Pharmacokinetics and pharmacodynamics of fluoroquinolones. Drugs. 1999; 58 Suppl 2:29-36. DOI: 10.2165/00003495-199958002-00006. View

12.

. Global leprosy update, 2013; reducing disease burden. Wkly Epidemiol Rec. 2014; 89(36):389-400. View

13.

Rocha A, Cunha M, Diniz L, Salgado C, Aires M, Nery J . Drug and multidrug resistance among Mycobacterium leprae isolates from Brazilian relapsed leprosy patients. J Clin Microbiol. 2012; 50(6):1912-7. PMC: 3372169. DOI: 10.1128/JCM.06561-11. View

14.

Matrat S, Cambau E, Jarlier V, Aubry A . Are all the DNA gyrase mutations found in Mycobacterium leprae clinical strains involved in resistance to fluoroquinolones?. Antimicrob Agents Chemother. 2007; 52(2):745-7. PMC: 2224767. DOI: 10.1128/AAC.01095-07. View

15.

Shimoda K, Ikeda T, Okawara S, Kato M . Possible relationship between phototoxicity and photodegradation of sitafloxacin, a quinolone antibacterial agent, in the auricular skin of albino mice. Toxicol Sci. 2000; 56(2):290-6. DOI: 10.1093/toxsci/56.2.290. View

16.

Man I, Murphy J, Ferguson J . Fluoroquinolone phototoxicity: a comparison of moxifloxacin and lomefloxacin in normal volunteers. J Antimicrob Chemother. 1999; 43 Suppl B:77-82. DOI: 10.1093/jac/43.suppl_2.77. View

17.

Disratthakit A, Doi N . In vitro activities of DC-159a, a novel fluoroquinolone, against Mycobacterium species. Antimicrob Agents Chemother. 2010; 54(6):2684-6. PMC: 2876381. DOI: 10.1128/AAC.01545-09. View

18.

Owens Jr R, Ambrose P . Antimicrobial safety: focus on fluoroquinolones. Clin Infect Dis. 2005; 41 Suppl 2:S144-57. DOI: 10.1086/428055. View

19.

Hoshino K, Inoue K, Murakami Y, Kurosaka Y, Namba K, Kashimoto Y . In vitro and in vivo antibacterial activities of DC-159a, a new fluoroquinolone. Antimicrob Agents Chemother. 2007; 52(1):65-76. PMC: 2223876. DOI: 10.1128/AAC.00853-07. View

20.

Dawe R, Ibbotson S, Sanderson J, Thomson E, Ferguson J . A randomized controlled trial (volunteer study) of sitafloxacin, enoxacin, levofloxacin and sparfloxacin phototoxicity. Br J Dermatol. 2003; 149(6):1232-41. DOI: 10.1111/j.1365-2133.2003.05582.x. View