Susceptibilities of Mycobacterium tuberculosis and Mycobacterium avium complex to lipophilic deazapteridine derivatives, inhibitors of dihydrofolate reductase

Abstract

Twelve lipophilic 2,4-diamino-5-methyl-5-deazapteridine derivatives and trimethoprim were evaluated for activity against Mycobacterium tuberculosis and Mycobacterium avium in vitro. Six of the compounds had MICs of < or =12.8 mg/L and < or =1.28 mg/L against M. tuberculosis and M. avium, respectively; trimethoprim MICs were >128 mg/L and >12.8 but < or =128 mg/L, respectively. Two compounds, with either a 2-methyl-5-methoxy phenyl or 2-methoxy-5-trifluoromethyl phenyl linked at the 6-position of the deazapteridine moiety by a CH2NH bridge, had MICs of < or =0.13 mg/L against M. avium; the two compounds also had apparent I50 values for dihydrofolate reductase of 2 and 8 nM, respectively, compared with an I50 of 400 nM with trimethoprim. Four of the compounds were selectively toxic to mycobacteria as compared with Vero cells. These results demonstrated that lipophilic antifolates can be synthesized which are more active against mycobacteria than trimethoprim and which possess selective toxicity.

Potential antimicrobial agents for the treatment of multidrug-resistant tuberculosis

“…There is ongoing debate about the use of SXT for the treatment of TB. Some studies mention that only SMX was effective against M. tuberculosis, while TMP is not [37,84].…”

Chemotherapeutic Strategies and Targets Against Resistant TB

“…Pathak et al (Pathak et al, 2003) synthesized several octyl 5-O-(-D-arabinofuranosyl)--Darabinofuranoside disaccharide analogs substituted at the 5-position of the non-reducing end of sugar and tested in vitro (Suling et al, 1998, as cited in Pathak et al, 2003 against Mtb (H37Ra, ATCC 25177), M. avium complex (MAC) as well as in a cell free assay system for arabinosyltransferase acceptor/inhibitor activity (Lee et al, 1997, as cited in Pathak et al, 2003. …”

Potentiation of Available Antibiotics by Targeting Resistance – An Emerging Trend in Tuberculosis Drug Development

“…Trimethoprim is commonly coadministered with sulfonamides, for example sulfamethoxazole in the co-trimoxazole combination, to achieve synergy (Libecco & Powell, 2004) (Figure 4). However, in many cases including that of M. tuberculosis, the synergistic effect of trimethoprim on sulfonamides remains questioned and inconclusive (Forgacs et al, 2009, Ong et al, 2010, Suling et al, 1998. In addition, bacterial strains resistant to both trimethoprim and sulfonamides have readily been isolated (Bermingham & Derrick, 2002, Gangjee et al, 2007, 2008.…”