Mutations in oxyR and oxyR-ahpC Interogenic Region in Isoniazid-Resistant Mycobacterium tuberculosis Clinical Isolates from Chongqing, China

Sen Yang,1,* Chao Xia,1,* Xiaoman Zheng,1 Yanqiu Lu,1 Jiaoyu Deng,2 Yaokai Chen1 1Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, People’s Republic of China; 2Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jiaoyu Deng, Email [email protected] Yaokai Chen, Email [email protected] and Aim: As a first line anti-tuberculosis drug, isoniazid (INH) has been extensively used for decades. Consequently, resistance of Mycobacterium tuberculosis (MTB) clinical isolates to INH is inevitably increasing and spreading, necessitating fast and accurate molecular diagnosis tools. Although many previous molecular epidemiological studies related with INH resistance included mutations in the oxyR-ahpC intergenic region, the role of mutations in the oxyR-ahpC intergenic region in INH resistance remains controversial. The present study aimed to investigate the frequency and distribution of mutations in the ahpC and the oxyR-ahpC intergenic region among INH-resistant Mycobacterium tuberculosis (MTB) clinical isolates in Chongqing, China.Methods: The presence of mutations in katG, ahpC and the oxyR-ahpC intergenic region was analyzed in 490 MTB clinical isolates.Results: None of the 73 INH-susceptible isolates (0%), 18 of 26 INH mono-resistant isolates (69.2%), 188 of 199 MDR (multidrug resistant) isolates (94.5%), and 176 of 192 pre-XDR/XDR (pre-extensively drug-resistant) isolates (91.7%) had mutations in katG. No mutations in ahpC, oxyR and the oxyR-ahpC intergenic region were identified in INH-susceptible and INH mono-resistant isolates. Mutations in the oxyR-ahpC intergenic region were rare (1.5% MDR, 1.04% pre-XDR), and only two mutations were identified (− 58 G→A in MDR and − 54 C→T in pre-XDR isolates). The former occurred in isolates with concurrent katG mutations, but the latter occurred in isolates without concurrent katG mutations. Notably, a novel Ala18Gly mutation in oxyR was identified in 3.52% of MDR and 6.77% of pre-XDR isolates.Conclusion: Mutation in katG is the main cause of INH resistance in MTB clinical strains isolated from Chongqing. It is very unlikely that mutation in the oxyR-ahpC intergenic region alone could cause INH resistance in MTB clinical isolates. Even though mutation in the oxyR-ahpC intergenic region could compensate the fitness cost of katG mutation, our finding that it is uncommon in MTB clinical isolates from Chongqing suggests it is not the primary compensatory mechanism. Further investigation is necessary to probe the relationship between mutations in the coding region of oxyR and INH resistance.Keywords: Mycobacterium tuberculosis, isoniazid, resistance, katG, oxyR-ahpC