Synergistic interactions of SQ109, a new ethylene diamine, with front-line antitubercular drugs in vitro.
OBJECTIVE
The purpose of this study was to determine interactions of SQ109, a new asymmetric diamine tuberculosis (TB) drug candidate, with existing antitubercular drugs in vitro and assess its potential to improve combination drug activities against Mycobacterium tuberculosis.


METHODS
Two-drug combinations at various concentrations below their MICs were tested for growth inhibition of M. tuberculosis using the BACTEC 460 system in vitro. Drug interactions were evaluated based on the quotient values that were derived numerically from the growth indices of cultures treated with a single antibiotic or combination treatment with two antibiotics.


RESULTS
SQ109 at 0.5 of its MIC demonstrated strong Synergistic activity with 0.5 MIC isoniazid and as low as 0.1 MIC rifampicin in inhibition of M. tuberculosis growth. Additive effects were observed between SQ109 and streptomycin, but neither synergy nor additive effects were observed with the combination of SQ109 with ethambutol or pyrazinamide. The synergy between SQ109 and rifampicin was also demonstrated using rifampicin-resistant (RIFR) M. tuberculosis strains; SQ109 lowered the MIC of rifampicin for these drug-resistant strains.


CONCLUSIONS
SQ109 interacts Synergistically with isoniazid and rifampicin, two of the most important front-line TB drugs. This finding supports efforts to further evaluate new combination therapies containing SQ109 in experimental animal models of TB that emulate future clinical trial studies in humans.
Chen
Ping
P
Sequella, Inc., 9610 Medical Center Drive Suite 200, Rockville, MD 20850, USA. chenpi@niaid.nih.gov
Gearhart
Jackie
J
Protopopova
Marina
M
Einck
Leo
L
Nacy
Carol A
CA
D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000995:Antitubercular Agents / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D004357:Drug Synergism; D005029:Ethylenediamines / Q000494:pharmacology*; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D012293:Rifampin / Q000494:pharmacology
D000995:Antitubercular Agents; D005029:Ethylenediamines; C506841:N-geranyl-N'-(2-adamantyl)ethane-1,2-diamine; D000218:Adamantane; D007538:Isoniazid; D012293:Rifampin