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In vivo evolution of drug-resistant Mycobacterium tuberculosis in patients during long-term treatment.

ABSTRACT: BACKGROUND:In the current scenario, the drug-resistant tuberculosis is a significant challenge in the control of tuberculosis worldwide. In order to investigate the in vivo evolution of drug-resistant M. tuberculosis, the present study envisaged sequencing of the draft genomes of 18 serial isolates from four pre-extensively drug-resistant (pre-XDR) tuberculosis patients for continuous genetic alterations. RESULTS:All of the isolates harbored single nucleotide polymorphisms (SNPs) ranging from 1303 to 1309 with M. tuberculosis H37Rv as the reference. SNPs ranged from 0 to 12 within patients. The evolution rates were higher than the reported SNPs of 0.5 in the four patients. All the isolates exhibited mutations at sites of known drug targets, while some contained mutations in uncertain drug targets including folC, proZ, and pyrG. The compensatory substitutions for rescuing these deleterious mutations during evolution were only found in RpoC I491T in one patient. Many loci with microheterogeneity showed transient mutations in different isolates. Ninety three SNPs exhibited significant association with refractory pre-XDR TB isolates. CONCLUSIONS:Our results showed evolutionary changes in the serial genetic characteristics of the pre-XDR TB patients due to accumulation of the fixed drug-resistant related mutations, and the transient mutations under continuous antibiotics pressure over several years.

SUBMITTER: Xu Y

PROVIDER: S-EPMC6116439 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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In vivo evolution of drug-resistant Mycobacterium tuberculosis in patients during long-term treatment.

Xu Yuhui Y Liu Fei F Chen Suting S Wu Jiannan J Hu Yongfei Y Zhu Baoli B Sun Zhaogang Z

BMC genomics 20180829 1

<h4>Background</h4>In the current scenario, the drug-resistant tuberculosis is a significant challenge in the control of tuberculosis worldwide. In order to investigate the in vivo evolution of drug-resistant M. tuberculosis, the present study envisaged sequencing of the draft genomes of 18 serial isolates from four pre-extensively drug-resistant (pre-XDR) tuberculosis patients for continuous genetic alterations.<h4>Results</h4>All of the isolates harbored single nucleotide polymorphisms (SNPs) ...[more]

PMID: 30157763

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Project description:Tuberculosis stands as a prominent cause of mortality in developing countries. The treatment of tuberculosis involves a complex procedure requiring the administration of a panel of at least four antimicrobial drugs for the duration of six months. The occurrence of treatment failure after the completion of a standard treatment course presents a serious medical problem. The purpose of this study was to evaluate antimicrobial drug resistant features of Mycobacterium tuberculosis associated with treatment failure. Additionally, it aimed to evaluate the effectiveness of second line drugs such as amikacin, linezolid, moxifloxacin, and the efflux pump inhibitor verapamil against M. tuberculosis isolates associated with treatment failure. We monitored 1200 tuberculosis patients who visited TB centres in Lahore and found that 64 of them were not cured after six months of treatment. Among the M. tuberculosis isolates recovered from the sputum of these 64 patients, 46 (71.9%) isolates were simultaneously resistant to rifampicin and isoniazid (MDR), and 30 (46.9%) isolates were resistant to pyrazinamide, Resistance to amikacin was detected in 17 (26,5%) isolates whereas resistance to moxifloxacin and linezolid was detected in 1 (1.5%) and 2 (3.1%) isolates respectively. Among MDR isolates, the additional resistance to pyrazinamide, amikacin, and linezolid was detected in 15(23.4%), 4(2.6%) and 1(1.56%) isolates respectively. One isolate simultaneously resistant to rifampicin, isoniazid, amikacin, pyrazinamide, and linezolid was also identified. In our investigations, the most frequently mutated amino acid in the treatment failure group was Serine 315 in katG. Three novel mutations were detected at codons 99, 149 and 154 in pncA which were associated with pyrazinamide resistance. The effect of verapamil on the minimum inhibitory concentration of isoniazid and rifampicin was observed in drug susceptible isolates but not in drug resistant isolates. Rifampicin and isoniazid enhanced the transcription of the efflux pump gene rv1258 in drug susceptible isolates collected from the treatment failure patients. Our findings emphasize a high prevalence of MDR isolates linked primarily to drug exposure. Moreover, the use of amikacin as a second line drug may not be the most suitable choice in such cases.

Project description:Gut microbiota dysbiosis has adverse health effects on human body. Multi-drug-resistant tuberculosis (MDR-TB) treatment uses a variety of antibiotics typically for more than 20 months, which may induce gut microbiota dysbiosis. The aim of this study is to investigate the long-term effects of MDR-TB treatment on human gut microbiota and its related health consequences. A total of 76 participants were recruited at a hospital in Linyi, China. The study included one active MDR-TB treatment group, one recovered group from MDR-TB and two treatment-naive tuberculosis groups as control. The two treatment-naïve tuberculosis groups were constructed to match the sex and the age of the active MDR-TB treatment and the recovered group, respectively. The fecal and blood samples were collected and analyzed for gut microbiota and metabolic parameters. An altered gut microbiota community and a loss of richness were observed during the MDR-TB treatment. Strikingly, 3-8 years after recovery and discontinuing the treatment, the gut microbiota still exhibited an altered taxonomic composition (p = 0.001) and a 16% decrease in richness (p = 0.018) compared to the gut microbiota before the treatment. The abundance of fifty-eight bacterial genera was significantly changed in the MDR-TB recovered group versus the untreated control group. Although there were persistent and pervasive gut microbiota alterations, no gastrointestinal symptom such as abdominal pain, diarrhea, nausea, flatulence, and constipation was observed in the recovered group. However, chronic disorders may be indicated by the elevated level of low-density lipoprotein cholesterol (LDLC) (p = 0.034) and total cholesterol (TC) (p = 0.017). These adverse lipid changes were associated with the altered gut bacterial taxa, including phylum Firmicutes and Verrucomicrobia and genera Adlercreutzia, Akkermansia, Butyricicoccus, Coprococcus, Clostridioides, Eubacterium, Erysipelatoclostridium, Fusicatenibacter, Klebsiella, Psychrobacter, and Streptococcus. Collectively, MDR-TB treatment induced a lasting gut microbiota dysbiosis, which was associated with unfavorable changes in lipid profile.

Dataset Information

In vivo evolution of drug-resistant Mycobacterium tuberculosis in patients during long-term treatment.

Publications

In vivo evolution of drug-resistant Mycobacterium tuberculosis in patients during long-term treatment.

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