Biology subjects

Shi, W.

Publications and source records attributed to Shi, W..

22 records · Page 2Linked to original sources

bioRxiv2017

Varying Effects of Common Tuberculosis Drugs on Enhancing Clofazimine Activity in vitro

Clofazimine (CFZ), originally developed as an anti-tuberculosis (TB) drug in the 1950s 1, is commonly used to treat leprosy and also nontuberculous mycobacterial (NTM) infections. 2 Although CFZ has good activity against Mycobacterium tuberculosis, it was not used in the treatment of pulmonary TB mainly because it had the side effect of skin discoloration and there were other more effective drugs like isoniazid (INH), rifampin (RIF) and pyrazinamide (PZA) already available for the treatment of TB. 2 However, the increasing emergence of multi-drug-resistant TB (MDR-TB) has revived interest in the use of CFZ to treat MDR-TB. 2,3\n\nAlthough resistance to CFZ has been shown to be mediated by mutations in Rv0678,4,5 Rv1979c, or Rv2535c (PepQ),5 the mode of action of CFZ has remained poorly understood. CFZ appears to hav ...

microbiology↗

bioRxiv2017

Identification of novel mutations associated with cycloserine resistance in Mycobacterium tuberculosis

ObjectivesD-cycloserine (DCS) is an important second-line drug used to treat multi-drug resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. However, the mechanisms of resistance to DCS are not well understood. Here we investigated the molecular basis of DCS resistance using in vitro isolated resistant mutants of Mycobacterium tuberculosis.\n\nMethodsM. tuberculosis H37Rv was subjected to mutant selection on 7H11 agar plates containing varying concentrations of DCS. A total of 35 DCS-resistant mutants were isolated and 18 mutants were subjected to whole genome sequencing. The identified mutations associated with DCS resistance were confirmed by PCR-Sanger sequencing.\n\nResultsWe identified mutations in 17 genes that are associated with DCS resistance. Except mutations in alr (rv3423c) which is known to be involved in DCS resistance, 16 new genes rv0059, betP (rv0917), rv0221, rv1403c, rv1683, rv1726, gabD2 (rv1731), rv2749, sugI (rv3331), hisC2 (rv3 772), single mutation in 5 intergenic region of rv3345c and rv1435c, and insertion in 3 region of rv0759c were identified as solo mutations in their respective DCS-resistant mutants. Our findings indicate that the mechanisms of DCS resistance are more complex than previously thought and involve genes participating in different cellular functions such as lipid metabolism, methyltransferase, stress response, and transport proteins.\n\nConclusionsNew mutations in diverse genes associated with DCS are identified, which shed new light on the mechanisms of action and resistance of DCS. Future studies are needed to verify these findings in clinical strains so that molecular detection of DCS resistance for improved treatment of MDR-TB can be developed.

microbiology↗

bioRxiv2017

Identification of drug candidates that enhance pyrazinamide activity from a clinical drug library

Tuberculosis (TB) remains a leading cause of morbidity and mortality globally despite the availability of the TB therapy. 1 The current TB therapy is lengthy and suboptimal, requiring a treatment time of at least 6 months for drug susceptible TB and 9-12 months (shorter Bangladesh regimen) or 18-24 months (regular regimen) for multi-drug-resistant tuberculosis (MDR-TB). 1 The lengthy therapy makes patient compliance difficult, which frequently leads to emergence of drug-resistant strains. The requirement for the prolonged treatment is thought to be due to dormant persister bacteria which are not effectively killed by the current TB drugs, except rifampin and pyrazinamide (PZA) which have higher activity against persisters. 2, 3 Therefore new therapies should address the problem of insufficient efficacy against M. tuberculosis persisters, which could cause relapse of clinical disease. 4 PZA is a critical frontline TB drug that kills persister bacteria 5 and shortens the TB treatment from 9-12 months to 6 months. 6, 7 Although several new TB drugs are showing promise in clinical studies, none can replace PZA as they all have to be used together with PZA. 7 Because of the essentiality of PZA and the high cost of developing new drugs, in this study, we explored the idea of identifying drugs that enhance the anti-persister activity of PZA as an economic alternative approach to developing new drugs for improved treatment by screening an clinical drug library against old M. tuberculosis cultures enriched with persisters.

microbiology↗

bioRxiv2017

Activity of Sulfa Drugs and Their Combinations against Stationary Phase B. burgdorferi in vitro

Lyme disease is a most common vector borne disease in the US. Although the majority of Lyme patients can be cured with the standard 2-4 week antibiotic treatment, at least 10-20% of patients continue to suffer from prolonged post-treatment Lyme disease syndrome (PTLDS). While the cause for this is unclear, one possibility is that persisting organisms are not killed by current Lyme antibiotics. In our previous studies, we screened an FDA drug library and an NCI compound library on B. burgdorferi and found some drug hits including sulfa drugs as having good activity against B. burgdorferi stationary phase cells. In this study, we evaluated the relative activity of three commonly used sulfa drugs sulfamethoxazole (Smx), dapsone (Dps), sulfachlorpyridazine (Scp), and also trimethoprim (Tmp), and assessed their combinations with the commonly prescribed Lyme antibiotics for activities against B. burgdorferi stationary phase cells. Using the same molarity concentration, dapsone, sulfachlorpyridazine and trimethoprim showed very similar activity against stationary phase B. burgdorferi enriched in persisters, however, sulfamethoxazole was the least active drug among the three sulfa drugs tested. Interestingly, contrary to other bacterial systems, Tmp did not show synergy in drug combinations with the three sulfa drugs at their clinically relevant serum concentrations against B. burgdorferi. We found that sulfa drugs combined with other antibiotics were more active than their respective single drugs and that four-drug combinations were more active than three-drug combinations. Four drug combinations dapsone+minocycline+cefuroxime+azithromycin and dapsone+minocycline+cefuroxime+rifampin showed best activity against stationary phase B. burgdorferi in these sulfa drug combinations. However, these 4-sulfa drug containing combinations still had considerably less activity against B. burgdorferi stationary phase cells than the daptomycin+cefuroxime+doxycycline used as a positive control which completely eradicated B. burgdorferi stationary phase cells. Future studies are needed to evaluate and optimize the sulfa drug combinations in vitro and also in animal models.

microbiology↗