Mechanisms and Action of Drug Resistance on <em>Mycobacterium tuberculosis</em>

Tuberculosis (TB) remains the most challenging infection to treat worldwide. The contemporary TB regimens consist of 6–9 months of daily doses of four drugs in the existing regimen that is extremely toxic to patients. The purpose of these longer treatments is to eliminate Mycobacterium tuberculosis, notorious for its ability to resist most antimycobacterial drugs, thereby preventing the formation of drug-resistant clinical strains. On the contrary, prolonged therapies have led to impoverished patient adherence. Furthermore, the severe limitations of drug choices have resulted in the emergence of drug-resistant strains. Unfortunately, the lack of great lethargy toward developing effective antituberculosis regimens with a large-scale prevalence rate is a tremendous challenge to controlling the pandemic. In fact, the current improvement in genomic studies for early diagnosis and understanding of drug resistance mechanisms, and the identification of newer drug targets, is remarkable and promising. Identifying genetic factors, chromosomal mutations, and associated pathways give new hope to current antituberculosis drug discovery. This focused review renders insights into understanding molecular mechanisms underlying the profound drug resistance. This knowledge is essential for developing effective, potent antibiotics against drug-resistant strains and helps shorten the current treatment courses required for drug-susceptible tuberculosis

Molecular Epidemiological Study of Pyrazinamide-Resistance in Clinical Isolates of Mycobacterium tuberculosis from South India

Pyrazinamide (PZA) has been in use for almost 50 years as a first-line drug for short-course chemotherapy against Mycobacterium tuberculosis. In this study, PCR mediated automated DNA sequencing is used to check the prevalence of PZA resistance among treatment failure cases of pulmonary tuberculosis. Out of 50 clinical isolates examined, 39 had mutations in the pncA gene that encodes Pyrazinamidase, an enzyme required to activate PZA. Of these, 31 (79.5%) were localized to three regions of pncA. We found two isolates with hitherto unreported mutation at amino acid 26 (Ala→Gly) of pncA

Risk Factors and Treatment Outcome Analysis Associated with Second-Line Drug-Resistant Tuberculosis

The present study aimed at analyzing the treatment outcomes and risk factors associated with fluoroquinolone drug resistance having mutations in the gyrA and gyrB genes. A total of 258 pulmonary tuberculosis samples with first-line drug-resistant (H, R, or HR) were subjected to GenoType MTBDRsl assay for the molecular detection of mutations. Among the 258 samples, 251 were drug-resistant tuberculosis and seven were sensitive to all first-line TB drugs. Out of 251 DR-TB cases, 42 cases were MDR TB, 200 were INH mono-resistant and nine cases were RIF mono-resistant tuberculosis. Out of 251 DR-TB cases performed with a MTBDRsl assay, 14 had Pre-XDR-FQ, one patient had pre-XDR-SLID, one had extensively drug-resistant tuberculosis (XDR-TB) and 235 cases were sensitive to both FQ and SLID drugs. The study group had a mean average of 42.7 &plusmn; 16.4 years. The overall successful treatment outcomes among the MDR, INH mono-resistant, and pre-XRD patients were 70.6%, 82.0%, and 51%, respectively. The percentage of risk for the unfavorable outcomes in the pre-XDR, INH -mono-resistant, and XDR cases were 113.84% increased risk with RR 2.14; 95% CI 0.7821&ndash;5.8468. The independent risk factor associated with the unfavorable outcomes to failure was 77.78% increased risk with RR 1.78; 95% CI 0.3375&ndash;9.3655. Logistic regression analysis revealed that the percentage relative risk among MDR-TB patients for gender, male (RR: 1.85), age &ge; 61 years (RR: 1.96), and diabetics (RR: 1.05) were 84.62%, 95.83%, and 4.76%, respectively. The independent risk factors associated with INH mono-resistant cases of age 16&ndash;60 (RR: 1.86), &ge;61 year (RR: 1.18), and treated cases (RR: 5.06). This study presaged the significant risk of INH mono-resistant, pre-XDR, and MDR among males, young adults, diabetics, and patients with previous treatment failure. Timely identification of high-risk patients will give pronounced advantages to control drug resistance tuberculosis diseases

Prevalence of mutations in genes associated with rifampicin and isoniazid resistance in Mycobacterium tuberculosis clinical isolates

Purpose: To analyze prevalence of mutations in genes associated with rifampicin and isoniazid resistance in Mycobacterium tuberculosis clinical isolates from patients with possible MDR TB of Puducherry, South India and to explore the association of specific mutations conferring rifampicin (RIF) resistance.Methods: We performed a commercial Genotype MDBDRplus V.2.0 assay for the rapid detection of rifampicin and isoniazid resistance directly on sputum specimens of patients with possible MDR TB.Results: Totally 558 multidrug resistant, 293 RIF mono resistant and 923 INH mono resistant tuberculosis were detected from the 12,786 patients with possible MDR TB samples. The 50.5% mutations were observed in the region of S531L in MDR TB patients and 55.6% in rifampicin monoresistant cases. In total isoniazid monoresistant, 68.0% mutations were detected in katG gene, which is more prevalent in comparison to inhA gene 32.0%. There were about 57.9% and 32.2% MDR TB cases diagnosed in the age group of >â15 to â¤â45 years and >â45 to â¤â60 years respectively.Conclusions: The rate of occurrences of mutations were found widely in the Rifampicin Resistant Determination Region (81bp) of rpoB gene and the hypervariable region 530â533 codons of rpoB gene is alarming in the specification. The higher frequency of mutation in codons of rpoB (S531L) and katG (S315T) gene help to design simple, new and less expensive molecular techniques to use in peripheral laboratories. Keywords: Mycobacterium tuberculosis, Multidrug resistant, Rifampicin monoresistant, Hypervariable region, Isoniazid monoresistan