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Antimicrobial Agents and Chemotherapy, February 2002, p. 443-450, Vol. 46, No. 2
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.2.443-450.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Molecular Characterization of Multidrug-Resistant Isolates of Mycobacterium tuberculosis from Patients in North India

Noman Siddiqi,1,2 Mohammed Shamim,2 Seema Hussain,2 Rakesh Kumar Choudhary,1 Niyaz Ahmed,1 Prachee,1 Sharmistha Banerjee,1 G. R. Savithri,1 Mahfooz Alam,1 Niteen Pathak,1 Amol Amin,2 Mohammed Hanief,3 V. M. Katoch,4 S. K. Sharma,5 and Seyed E. Hasnain1,2,6*

Centre for DNA Fingerprinting and Diagnostics, Hyderabad 500076,1 National Institute of Immunology,2 New Delhi TB Centre,3 Department of Medicine, A.I.I.M.S.,5 New Delhi, Central Jalma Institute of Leprosy, Agra,4 Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560064, India6

Received 17 April 2001/ Returned for modification 29 June 2001/ Accepted 1 November 2001

The World Health Organization has identified India as a major hot-spot region for Mycobacterium tuberculosis infection. We have characterized the sequences of the loci associated with multidrug resistance in 126 clinical isolates of M. tuberculosis from India to identify the respective mutations. The loci selected were rpoB (rifampin), katG and the ribosomal binding site of inhA (isoniazid), gyrA and gyrB (ofloxacin), and rpsL and rrs (streptomycin). We found known as well as novel mutations at these loci. Few of the mutations at the rpoB locus could be correlated with the drug resistance levels exhibited by the M. tuberculosis isolates and occurred with frequencies different from those reported earlier. Missense mutations at codons 526 to 531 seemed to be crucial in conferring a high degree of resistance to rifampin. We identified a common Arg463Leu substitution in the katG locus and certain novel insertions and deletions. Mutations were also mapped in the ribosomal binding site of the inhA gene. A Ser95Thr substitution in the gyrA locus was the most common mutation observed in ofloxacin-resistant isolates. A few isolates showed other mutations in this locus. Seven streptomycin-resistant isolates had a silent mutation at the lysine residue at position 121. While certain mutations are widely present, pointing to the magnitude of the polymorphisms at these loci, others are not common, suggesting diversity in the multidrug-resistant M. tuberculosis strains prevalent in this region. Our results additionally have implications for the development of methods for multidrug resistance detection and are also relevant in the shaping of future clinical treatment regimens and drug design strategies.

* Corresponding author. Mailing address: C.D.F.D., ECIL Rd., Nacharam, Hyderabad-500 076, India. Phone: 91-040 7155604 or 91-040 7155605. Fax: 91-040 7155610 or 91-040 7155479. E-mail: director{at}www.cdfd.org.in.

Antimicrobial Agents and Chemotherapy, February 2002, p. 443-450, Vol. 46, No. 2
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.2.443-450.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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