Modification of Rifamycin Polyketide Backbone Leads to Improved Drug Activity Against Rifampicin-resistant Mycobacterium Tuberculosis

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2014 Jun 14

PMID 24923585

Citations 24

Authors

Aeshna Nigam

Khaled H Almabruk

Anjali Saxena

Jongtae Yang

Udita Mukherjee

Hardeep Kaur

Puneet Kohli

Rashmi Kumari

Priya Singh

Lev N Zakharov

Yogendra Singh

Taifo Mahmud

Rup Lal

Affiliations

Soon will be listed here.

Abstract

Rifamycin B, a product of Amycolatopsis mediterranei S699, is the precursor of clinically used antibiotics that are effective against tuberculosis, leprosy, and AIDS-related mycobacterial infections. However, prolonged usage of these antibiotics has resulted in the emergence of rifamycin-resistant strains of Mycobacterium tuberculosis. As part of our effort to generate better analogs of rifamycin, we substituted the acyltransferase domain of module 6 of rifamycin polyketide synthase with that of module 2 of rapamycin polyketide synthase. The resulting mutants (rifAT6::rapAT2) of A. mediterranei S699 produced new rifamycin analogs, 24-desmethylrifamycin B and 24-desmethylrifamycin SV, which contained modification in the polyketide backbone. 24-Desmethylrifamycin B was then converted to 24-desmethylrifamycin S, whose structure was confirmed by MS, NMR, and X-ray crystallography. Subsequently, 24-desmethylrifamycin S was converted to 24-desmethylrifampicin, which showed excellent antibacterial activity against several rifampicin-resistant M. tuberculosis strains.

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References

Lal R, Lal S, Grund E, Eichenlaub R . Construction of a hybrid plasmid capable of replication in Amycolatopsis mediterranei. Appl Environ Microbiol. 1991; 57(3):665-71. PMC: 182777. DOI: 10.1128/aem.57.3.665-671.1991. View

Khanna M, Dua M, Lal R . Selection of suitable marker genes for the development of cloning vectors and electroporation in different strains of Amycolatopsis mediterranei. Microbiol Res. 1999; 153(3):205-11. DOI: 10.1016/S0944-5013(98)80002-5. View

Verma M, Kaur J, Kumar M, Kumari K, Saxena A, Anand S . Whole genome sequence of the rifamycin B-producing strain Amycolatopsis mediterranei S699. J Bacteriol. 2011; 193(19):5562-3. PMC: 3187414. DOI: 10.1128/JB.05819-11. View

Kim C, Yu T, Fryhle C, Handa S, Floss H . 3-Amino-5-hydroxybenzoic acid synthase, the terminal enzyme in the formation of the precursor of mC7N units in rifamycin and related antibiotics. J Biol Chem. 1998; 273(11):6030-40. DOI: 10.1074/jbc.273.11.6030. View

Yu T, Shen Y, Tang L, Park C, Moore B, Hutchinson C . Direct evidence that the rifamycin polyketide synthase assembles polyketide chains processively. Proc Natl Acad Sci U S A. 1999; 96(16):9051-6. PMC: 17730. DOI: 10.1073/pnas.96.16.9051. View

Xue Q, Ashley G, Hutchinson C, Santi D . A multiplasmid approach to preparing large libraries of polyketides. Proc Natl Acad Sci U S A. 1999; 96(21):11740-5. PMC: 18356. DOI: 10.1073/pnas.96.21.11740. View

Lal R, Khanna R, Kaur H, Khanna M, Dhingra N, Lal S . Engineering antibiotic producers to overcome the limitations of classical strain improvement programs. Crit Rev Microbiol. 1996; 22(4):201-55. DOI: 10.3109/10408419609105481. View

Schupp T, Toupet C, Engel N, Goff S . Cloning and sequence analysis of the putative rifamycin polyketide synthase gene cluster from Amycolatopsis mediterranei. FEMS Microbiol Lett. 1998; 159(2):201-7. DOI: 10.1111/j.1574-6968.1998.tb12861.x. View

Wilson M, Gulder T, Mahmud T, Moore B . Shared biosynthesis of the saliniketals and rifamycins in Salinispora arenicola is controlled by the sare1259-encoded cytochrome P450. J Am Chem Soc. 2010; 132(36):12757-65. PMC: 2946249. DOI: 10.1021/ja105891a. View

10.

Admiraal S, WALSH C, Khosla C . The loading module of rifamycin synthetase is an adenylation-thiolation didomain with substrate tolerance for substituted benzoates. Biochemistry. 2001; 40(20):6116-23. DOI: 10.1021/bi010080z. View

11.

Lal R, Kumari R, Kaur H, Khanna R, Dhingra N, Tuteja D . Regulation and manipulation of the gene clusters encoding type-I PKSs. Trends Biotechnol. 2000; 18(6):264-74. DOI: 10.1016/s0167-7799(00)01443-8. View

12.

Khosla C, Kapur S, Cane D . Revisiting the modularity of modular polyketide synthases. Curr Opin Chem Biol. 2009; 13(2):135-43. PMC: 2737389. DOI: 10.1016/j.cbpa.2008.12.018. View

13.

Ruan X, Pereda A, Stassi D, Zeidner D, Summers R, Jackson M . Acyltransferase domain substitutions in erythromycin polyketide synthase yield novel erythromycin derivatives. J Bacteriol. 1997; 179(20):6416-25. PMC: 179558. DOI: 10.1128/jb.179.20.6416-6425.1997. View

14.

Floss H . Combinatorial biosynthesis--potential and problems. J Biotechnol. 2006; 124(1):242-57. PMC: 1865499. DOI: 10.1016/j.jbiotec.2005.12.001. View

15.

Gaisser S, Bohm G, Cortes J, Leadlay P . Analysis of seven genes from the eryAI-eryK region of the erythromycin biosynthetic gene cluster in Saccharopolyspora erythraea. Mol Gen Genet. 1997; 256(3):239-51. DOI: 10.1007/s004380050566. View

16.

Staunton J, Weissman K . Polyketide biosynthesis: a millennium review. Nat Prod Rep. 2001; 18(4):380-416. DOI: 10.1039/a909079g. View

17.

Williams D, Spring L, Collins L, MILLER L, Heifets L, GANGADHARAM P . Contribution of rpoB mutations to development of rifamycin cross-resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 1998; 42(7):1853-7. PMC: 105697. DOI: 10.1128/AAC.42.7.1853. View

18.

Ranganathan A, Timoney M, Bycroft M, Cortes J, Thomas I, Wilkinson B . Knowledge-based design of bimodular and trimodular polyketide synthases based on domain and module swaps: a route to simple statin analogues. Chem Biol. 1999; 6(10):731-41. DOI: 10.1016/s1074-5521(00)80020-4. View

19.

Campbell E, Korzheva N, Mustaev A, Murakami K, Nair S, Goldfarb A . Structural mechanism for rifampicin inhibition of bacterial rna polymerase. Cell. 2001; 104(6):901-12. DOI: 10.1016/s0092-8674(01)00286-0. View

20.

Stratmann A, Toupet C, Schilling W, Traber R, Oberer L, Schupp T . Intermediates of rifamycin polyketide synthase produced by an Amycolatopsis mediterranei mutant with inactivated rifF gene. Microbiology (Reading). 2000; 145 ( Pt 12):3365-3375. DOI: 10.1099/00221287-145-12-3365. View