Impact of Hypoxia on Drug Resistance and Growth Characteristics of Mycobacterium tuberculosis Clinical Isolates.
Mycobacterium tuberculosis (MTB) is a specific aerobic bacterium, but can survive under hypoxic conditions, such as those in lung cheese necrosis, granulomas, or macrophages. It is not clear whether the drug sensitivity and growth characteristics of MTB under hypoxic conditions are different from those under aerobic conditions. In this study, we examined the drug resistance and growth characteristics of MTB clinical isolates by a large sample of in vitro drug susceptibility tests, using an automatic growth instrument. Under hypoxic conditions, variance in drug resistance was observed in nearly one-third of the MTB strains and was defined as MTB strains with changed drug sensitivity (MTB-CDS). Among these strains, resistance in a considerable proportion of clinical strains was significantly increased, and some strains emerged as multi-drug resistant. Growth test results revealed a high growth rate and large survival number in macrophages under hypoxia in MTB-CDS. According to the results of fluorescence quantitative PCR, the expression of some genes, including RegX3 (involving RIF resistance), Rv0194 (efflux pump gene), four genes related to transcription regulation (KstR, DosR, Rv0081 and WhiB3) and gene related to translation regulation (DATIN), were upregulated significantly under hypoxic conditions compared to that under aerobic conditions (p < 0.05). Thus, we concluded that some MTB clinical isolates can survive under hypoxic conditions and their resistance could change. As for poor clinical outcomes in patients, based on routine drug susceptibility testing, drug susceptibility tests for tuberculosis under hypoxic conditions should also be recommended. However, the detailed mechanisms of the effect of hypoxia on drug sensitivity and growth characteristics of MTB clinical isolates still requires further study.
Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
Zhonghua
Z
Liu
Department of Laboratory Medicine, Kunshan Hospital Affiliated to Nanjing University of Traditional Chinese Medicine, Kunshan, China.
Yulu
Y
Gao
Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
Hua
H
Yang
Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
Haiyang
H
Bao
Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
Lianhua
L
Qin
Department of Transfusion, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Changtai
C
Zhu
Department of Nursing, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Yawen
Y
Chen
Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
Zhongyi
Z
Hu
D000332:Aerobiosis; D000693:Anaerobiosis; D001426:Bacterial Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D011494:Protein Kinases / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics; D014376:Tuberculosis / Q000382:microbiology
D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; C542863:DosR protein, Mycobacterium tuberculosis; C110608:RegX3 protein, Mycobacterium; D014157:Transcription Factors; D011494:Protein Kinases