Research Article

Synergistic effect of doripenem in combination with cefoxitin and tetracycline in inhibiting NDM-1 producing bacteria

Medical Microbiology & Molecular Biology Laboratory, Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, Uttar Pradesh, 202002, India

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Shamsi Khalid

Medical Microbiology & Molecular Biology Laboratory, Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, Uttar Pradesh, 202002, India

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Abid Ali

Medical Microbiology & Molecular Biology Laboratory, Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, Uttar Pradesh, 202002, India

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Asad U Khan

*Author for correspondence: Tel.: +91 983 702 1912; Fax: +91 571 272 1776;

E-mail Address: asad.k@rediffmail.com

https://orcid.org/0000-0001-9191-9423

Medical Microbiology & Molecular Biology Laboratory, Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, Uttar Pradesh, 202002, India

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Published Online:4 Jun 2019https://doi.org/10.2217/fmb-2019-0032

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Abstract

Aim: To propose newer combinations of antibiotics effective against NDM-1-producing bacterial strains. Materials & methods: Antibiotics combinations were tested by checkerboard assay. NDM-1 protein/enzyme was expressed and purified to perform enzyme kinetics, circular dichroism and fluorescence spectroscopic studies. Results: Doripenem–cefoxitin combination and doripenem–tetracycline combination showed synergistic effect toward NDM-1-producing strains. The catalytic efficiency of NDM-1 enzyme was decreased drastically by 96.6% upon doripenem–cefoxitin treatment and by 35.54% after doripenem–tetracycline treatment. Conformational changes were observed in NDM-1 upon combination treatment. Conclusion: NDM-1-producing bacterial strains show resistance to multiple antibiotics but the combination of doripenem–cefoxitin and doripenem–tetracycline are effective against them. The combination of a carbapenem and cephamycin antibiotic is proposed for future treatment options against bacteria-producing NDM-1.

Keywords:

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1. Paterson DL, Bonomo RA. Extended-spectrum β-lactamases: a clinical update. Clin. Microbiol. Rev. 18(4), 657–686 (2005).
Medline CASGoogle Scholar
2. Chouchani C, Marrakchi R, El Salabi A. Evolution of β-lactams resistance in Gram-negative bacteria in Tunisia. Crit. Rev. Microbiol. 37(3), 167–177 (2011).
Medline CASGoogle Scholar
3. Queenan AM, Bush K. Carbapenemases: the versatile β-lactamases. Clin. Microbiol. Rev. 20(3), 440–458 (2007). • Comprehensive review updating charactersitics, epidemiology and detection of carabapenemases found in different pathogenic bacteria.
Medline CASGoogle Scholar
4. King DT, Worrall LJ, Gruninger R, Strynadka NC. New Delhi metallo-β-lactamase: structural insights into β-lactam recognition and inhibition. J. Am. Chem. Soc. 134(28), 11362–11365 (2012). • Paper reports an analysis of active site of NDM-1 and the key features important for designing of novel inhibitors against it.
Medline CASGoogle Scholar
5. Khan AU, Maryam L, Zarrilli R. Structure, genetics and worldwide spread of New Delhi metallo-β-lactamase (NDM): a threat to public health. BMC Microbiol. 17(1), 101 (2017). •• Recent and comprehensive review on NDM and its variants harboring bacterial strains and threats they cause to public health.
MedlineGoogle Scholar
6. Rolain JM, Parola P, Cornaglia G. New Delhi metallo-beta-lactamase (NDM-1): toward a new pandemia? Clin. Microbiol. Infect. 16(12), 1699–1701 (2010). • Report of alarming risk of NDM-1 gene spreading in Enterobacteriaceae and uncontrollable spread of pandemic NDM-1 clones.
Medline CASGoogle Scholar
7. Feng H, Liu X, Wang S, Fleming J, Wang DC, Liu W. The mechanism of NDM-1-catalyzed carbapenem hydrolysis is distinct from that of penicillin or cephalosporin hydrolysis. Nat. Commun. 8(1), 2242 (2017).
MedlineGoogle Scholar
8. Brogden RN, Heel RC, Speight TM, Avery GS. Cefoxitin: a review of its antibacterial activity, pharmacological properties and therapeutic use. Drugs 17(1), 1–37 (1979).
Medline CASGoogle Scholar
9. Makena A, Brem J, Pfeffer I et al. Biochemical characterization of New Delhi metallo-β-lactamase variants reveals differences in protein stability. J. Antimicrob. Chemother. 70(2), 463–469 (2014).
MedlineGoogle Scholar
10. Poirel L, Dortet L, Bernabeu S, Nordmann P. Genetic features of blaNDM-1-positive Enterobacteriaceae. Antimicrob. Agents Chemother. 55, 5403–5407 (2011).
Medline CASGoogle Scholar
11. Uppu DS, Manjunath GB, Yarlagadda V et al. Membrane-active macromolecules resensitize NDM-1 Gram-negative clinical isolates to tetracycline antibiotics. PLoS ONE 10(3), e0119422 (2015).
MedlineGoogle Scholar
12. Maryam L, Khan AU. Combination of aztreonam and cefotaxime against CTX-M-15 type β-lactamases: a mechanism based effective therapeutic approach. Int. J. Biol. Macromol. 116, 1186–1195 (2018). •• Recent information about synergistic effect of combination therapy against β-lactamases producing strain.
Medline CASGoogle Scholar
13. Maryam L, Khan AU. Synergistic effect of doripenem and cefotaxime to inhibit CTX-M-15 type β-lactamases: Biophysical and microbiological views. Front. Pharmacol. 8, 449 (2017). •• Recent information about synergistic effect of combination therapy against β-lactamases-producing strain.
MedlineGoogle Scholar
14. Maryam L, Khan AU. A mechanism of synergistic effect of streptomycin and cefotaxime on CTX-M-15 Type β-lactamase producing strain of E. cloacae: a first report. Front. Microbiol. 7, 2007 (2016). •• Recent information about synergistic effect of combination therapy against β-lactamases-producing strain.
MedlineGoogle Scholar
15. Ali A, Azam MW, Khan AU. Non-active site mutation (Q123A) in New Delhi metallo-β-lactamase (NDM-1) enhanced its enzyme activity. Int. J. Biol. Macromol. 112, 1272–1277 (2018).
Medline CASGoogle Scholar
16. Shen B, Yu Y, Chen H et al. Inhibitor discovery of full-length New Delhi metallo-β-lactamase-1 (NDM-1). PLoS ONE 8(5), e62955 (2013).
Medline CASGoogle Scholar
17. Khan AU, Rehman MT. Role of non-active-site residue Trp-93 in the function and stability of New Delhi metallo-β-lactamase 1. Antimicrob. Agents Chemother. 60(1), 356–360 (2016).
Medline CASGoogle Scholar
18. Wayne PA. Performance standards for antimicrobial susceptibility testing: 21st informational supplement. M100-S21. Clinical & Laboratory Standards Institute (2011). https://books.google.co.in/books/about/Performance_Standards_for_Antimicrobial.html?id=eeX2tgAACAAJ&redir_esc=y
Google Scholar
19. Hasan S, Ali SZ, Khan AU. Novel combinations of antibiotics to inhibit extended-spectrum β-lactamase and metallo-β-lactamase producers in vitro: a synergistic approach. Future Microbiol. 8(7), 939–944 (2013). • Novel synergistic combinations are proposed against different resistant strains.
CASGoogle Scholar
20. Galleni M, Franceschini N, Quinting B et al. Use of the chromosomal class A beta-lactamase of Mycobacterium fortuitum D316 to study potentially poor substrates and inhibitory beta-lactam compounds. Antimicrob. Agents Chemother. 38(7), 1608–1614 (1994).
Medline CASGoogle Scholar
21. Ishtikhar M, Usmani SS, Gull N, Badr G, Mahmoud MH, Khan RH. Inhibitory effect of copper nanoparticles on rosin modified surfactant induced aggregation of lysozyme. Int. J. Biol. Macromol. 78, 379–388 (2015).
Medline CASGoogle Scholar
22. Maryam L, Khan AU. Structural insight into mode of binding of meropenem to CTX-M-15 type β-lactamase. 96, 78–86 (2017).
Google Scholar
23. Ali A, Danishuddin, Maryam L, Srivastava G, Sharma A, Khan AU. Designing of inhibitors against CTX-M-15 type β-lactamase: potential drug candidate against β-lactamases-producing multidrug-resistant bacteria. J. Biomol. Struct. Dyn. 36(7), 1806–1821 (2018).
Medline CASGoogle Scholar
24. Maryam L, Sharma A, Azam MW, Khan SN, Khan AU. Understanding the mode of binding mechanism of doripenem to human serum albumin: spectroscopic and molecular docking approaches. J. Mol. Recognit. 31(7), e2710 (2018).
MedlineGoogle Scholar
25. Alam MF, Laskar AA, Maryam L, Younus H. Activation of human salivary aldehyde dehydrogenase by sulforaphane: mechanism and significance. PLoS ONE 11(12), e0168463 (2016).
MedlineGoogle Scholar
26. Kang J, Liu Y, Xie MX, Li S, Jiang M, Wang YD. Interactions of human serum albumin with chlorogenic acid and ferulic acid. Biochim. Biophys. Acta 1674(2), 205–214 (2004).
Medline CASGoogle Scholar
27. Mocz G, Ross RA. Fluorescence techniques in analysis of protein–ligand interactions. Methods Mol. Biol. 1008 , 169–210 (2013).
Medline CASGoogle Scholar
28. Munita JM, Arias CA. Mechanisms of antibiotic resistance. Microbiol. Spectr. 4(2), doi:10.1128/microbiolspec.VMBF-0016-2015 (2016).
MedlineGoogle Scholar
29. Kohanski MA, Dwyer DJ, Collins JJ. How antibiotics kill bacteria: from targets to networks. Nat. Rev. Microbiol. 8(6), 423 (2010).
Medline CASGoogle Scholar
30. Maryam L, Khalid S, Ali A, Khan AU. Significant role of Asn-247 and Arg-64 residues in close proximity of the active site in maintaining the catalytic function of CTX-M-15 type β-lactamase. RSC Adv. 9(10), 5325–5337 (2019).
CASGoogle Scholar
31. Sridharan R, Zuber J, Connelly SM, Mathew E, Dumont ME. Fluorescent approaches for understanding interactions of ligands with G protein coupled receptors. Biochim. Biophys. Acta 1838(1), 15–33 (2014).
Medline CASGoogle Scholar
32. Cao X, He Y, Liu D et al. Characterization of interaction between scoparone and bovine serum albumin: spectroscopic and molecular docking methods. RSC Advances 8(45), 25519–25525 (2018).
CASGoogle Scholar
33. Croney JC, Jameson DM, Learmonth RP. Fluorescence spectroscopy in biochemistry: teaching basic principles with visual demonstrations. Biochem. Mol. Biol. Edu. 29(2), 60–65 (2001).
CASGoogle Scholar
34. Möller M, Denicola A. Protein tryptophan accessibility studied by fluorescence quenching. Biochem. Mol. Biol. Edu. 30(3), 175–178 (2002).
CASGoogle Scholar
35. Rehman MT, Shamsi H, Khan AU. Insight into the binding mechanism of imipenem to human serum albumin by spectroscopic and computational approaches. Mol. Pharm. 11(6), 1785–1797 (2014).
Medline CASGoogle Scholar

Vol. 14, No. 8

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History

Received 31 January 2019

Accepted 4 April 2019

Published online 4 June 2019

Published in print May 2019

Information

Keywords

Author contributions

L Maryam conceived the idea, performed all the experiments, data curation, calculations and graph plotting and also wrote the manuscript; S Khalid helped in protein purification, MIC and fluorescence experiments; A Ali helped in protein purification experiment; and AU Khan designed the study and guided and checked the manuscript.

Acknowledgments

The author acknowledges the support of Interdisciplinary Biotechnology Unit, Aligarh Muslim University under DST-PURSE Phase II.

Financial & competing interests disclosure

The work was supported by internal funds of Interdisciplinary Biotechnology Department. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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