A microbiological assessment of novel nitrofuranylamides as anti-tuberculosis agents

Hurdle, Julian G.; Lee, Robin B.; Budha, Nageshwar; Carson, Elizabeth I.; Qi, Jianjun; Scherman, Michael S.; Cho, Sang Hyun; McNeil, Michael; Lenaerts, Anne J.; Franzblau, Scott G.; Meibohm, Bernd; Lee, Richard

doi:10.1093/jac/dkn307

Cited by 96 publications

(88 citation statements)

References 34 publications

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“…d PA-824-resistant mutant; a 400-bp deletion in fbiC is responsible for resistance, and complementation with wild-type fbiC restores susceptibility (19,25). e PA-824-resistant mutant; complementation with wild-type ddn restores susceptibility (19,25).…”

Section: T Deletion At Nucleotide Position 38 ͼ32mentioning

confidence: 99%

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Impact of fgd1 and ddn Diversity in Mycobacterium tuberculosis Complex on In Vitro Susceptibility to PA-824

Feuerriegel

Köser

Baù

et al. 2011

Antimicrob Agents Chemother

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PA-824 is a promising drug candidate for the treatment of tuberculosis (TB). It is in phase II clinical trials as part of the first newly designed regimen containing multiple novel antituberculosis drugs (PA-824 in combination with moxifloxacin and pyrazinamide). However, given that the genes involved in resistance against PA-824 are not fully conserved in theMycobacterium tuberculosiscomplex (MTBC), this regimen might not be equally effective against different MTBC genotypes. To investigate this question, we sequenced two PA-824 resistance genes (fgd1[Rv0407] andddn[Rv3547]) in 65 MTBC strains representing major phylogenetic lineages. The MICs of representative strains were determined using the modified proportion method in the Bactec MGIT 960 system. Our analysis revealed single-nucleotide polymorphisms in both genes that were specific either for several genotypes or for individual strains, yet none of these mutations significantly affected the PA-824 MICs (≤0.25 μg/ml). These results were supported byin silicomodeling of the mutations identified in Fgd1. In contrast, “Mycobacterium canettii” strains displayed a higher MIC of 8 μg/ml. In conclusion, we found a large genetic diversity in PA-824 resistance genes that did not lead to elevated PA-824 MICs. In contrast,M. canettiistrains had MICs that were above the plasma concentrations of PA-824 documented so far in clinical trials. AsM. canettiiis also intrinsically resistant against pyrazinamide, new regimens containing PA-824 and pyrazinamide might not be effective in treatingM. canettiiinfections. This finding has implications for the design of multiple ongoing clinical trials.

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Section: T Deletion At Nucleotide Position 38 ͼ32mentioning

confidence: 99%

“…Moreover, we performed in silico modeling of the mutations in Fgd1 using the previously solved crystal structure of this protein (4). We included three PA-824-resistant positive controls (H37Rv-T3, H37Rv-5A1, and H37Rv-14A1) which had been previously analyzed genotypically and phenotypically (19,25).…”

mentioning

confidence: 99%

Impact of fgd1 and ddn Diversity in Mycobacterium tuberculosis Complex on In Vitro Susceptibility to PA-824

Feuerriegel

Köser

Baù

et al. 2011

Antimicrob Agents Chemother

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“…The effects of the analogs on exponentially growing S. aureus 8325 and membrane integrity were evaluated as described previously (11). Cytotoxicity was evaluated by exposing normal CCD-32Sk human skin fibroblast cells (ATCC, Manassas, VA) to antibiotics for 48 h, followed by an MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide] assay as described previously (8).…”

mentioning

confidence: 99%

Evaluation of Analogs of Reutericyclin as Prospective Candidates for Treatment of Staphylococcal Skin Infections

Hurdle

Yendapally

Sun

et al. 2009

Antimicrob Agents Chemother

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The potential for reutericyclin derivatives to be used as topical antibiotics to treat staphylococcal skin infections was investigated. All reutericyclins inhibited the growth of clinical isolates of drug-resistant Staphylococcus aureus. Unlike the standard topical agent mupirocin, most reutericyclin derivatives eradicated staphylococcal biofilms. Moreover, two compounds formulated in hydrophilic petrolatum (10%, wt/wt) were efficacious in treating S. aureus superficial skin infections in mice. These data exemplify the prospect of developing reutericyclins as new topical antibiotics.

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“…With the same interest, the efficacy of anti-TB, 5-nitrofuranylamides NFAs (29a-e) against TB complex and other clinically relevant nonmycobacterial species [51] and found that the NFAs were significantly active against Mtb complex [52][53][54][55]. Compound 29a showed preeminent inhibition of MIC 0.006 mg/L against Mtb UT30 (streptomycin resistant at 4 mg/L).…”

Section: Piperazine and Pyrazine Derivativesmentioning

confidence: 96%

Recent Efforts for the Development of Antitubercular Drug Containing Diazine Ring

Asif¹

2012

Med chem

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There has been considerable interest in the development of new molecule with antibacterial activities particularly against tuberclosis because mycobacterium species have developed resistant against currently used drugs, their toxic effect and long duration of therapy. The diazine (pyridazine, pyrimidine and piperazine) derivatives possess an important class of compound for new drugs research and development. Therefore, many researchers have synthesized these compounds as target structures and evaluated their antitubercular activity. These observations have been guiding for the development of new molecules that possess potent antitubercular activity with minimum side effects or effective against MDR, XDR mycobacterium strains, and also in patient co-infected with HIV/AIDS.

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A microbiological assessment of novel nitrofuranylamides as anti-tuberculosis agents

Cited by 96 publications

References 34 publications

Impact of fgd1 and ddn Diversity in Mycobacterium tuberculosis Complex on In Vitro Susceptibility to PA-824

Impact of fgd1 and ddn Diversity in Mycobacterium tuberculosis Complex on In Vitro Susceptibility to PA-824

Evaluation of Analogs of Reutericyclin as Prospective Candidates for Treatment of Staphylococcal Skin Infections

Recent Efforts for the Development of Antitubercular Drug Containing Diazine Ring

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