Activities of poloxamer CRL8131 against Mycobacterium tuberculosis in vitro and in vivo

Abstract

A poloxamer surfactant, CRL8131, was evaluated for activity against Mycobacterium tuberculosis (Erdman) by itself and in combination with antibiotics in broth culture, in a macrophage cell line assay, and in testing with mice. In the broth culture, CRL8131 suppressed the growth of M. tuberculosis and produced synergistic effects in combination with isoniazid, rifampin, and streptomycin. It also displayed synergy with isoniazid and rifampin against two drug-resistant isolates. In the macrophage cell line assay, CRL8131 produced a synergistic effect on intracellular killing of M. tuberculosis by isoniazid, rifampin, streptomycin, pyrazinamide, thiacetazone, D-cycloserine, ethionamide, amikacin, clindamycin, and p-aminosalicylic acid. It demonstrated no synergy or antagonism with ethambutol, gentamicin, kanamycin, ciprofloxacin, or nalidixic acid. Finally, with C57BL/6 mice infected with M. tuberculosis, a combination of CRL8131 and either thiacetazone or pyrazinamide produced 100% survival at 40 days whereas the antibiotics produced only 33% survival and CRL8131 produced 0% survival when used as single agents. This improved survival rate was associated with a significant reduction in the number of organisms in the lungs and spleens of infected mice.The feasibility of using large hydrophobic nonionic surfactants for treating mice infected with Mycobacterium tuberculosis was demonstrated over 40 years ago. Cornforth et al. reported that a single injection of Triton WR-1339 significantly prolonged the survival of mice infected intravenously with a large dose of M. tuberculosis organisms (6,8). The injection of a surfactant was effective if given either before or up to 5 days after infection. The surfactant suppressed growth of M. tuberculosis in macrophage cultures and in intact mice but was inactive in broth culture. It was found to localize in macrophages after systemic injection (20). This information led to the hypothesis that Triton WR-1339 and similar agents suppressed tuberculosis infection by modulating host-parasite interactions rather than by direct action on the organism. It was reported further that Triton WR-1339 produced a synergistic suppression of M. tuberculosis growth in mice when used in combination with rifampin and pyrazinamide (19). In spite of these promising findings, the development of surfactants as drugs was not pursued because of the discovery of more effective drugs and declining interest in the disease. However, the increasing incidence of disease in immunocompromised people and the emergence of multidrug-resistant strains of M. tuberculosis have renewed interest in novel antimycobacterial agents.We have investigated the biologic activities of poloxamers for over 10 years. Poloxamers are simple synthetic surfactants that consist of a central chain of hydrophobic polyoxypropylene (POP) flanked by two chains of hydrophilic polyoxyethylene (POE) (22). By varying the lengths of these chains, a homologous series of compounds which span nearly the entire spectrum of functional properties of no...

Disruption of the Genes Encoding Antigen 85A and Antigen 85B of Mycobacterium tuberculosis H37Rv: Effect on Growth in Culture and in Macrophages

“…7). These results are similar to those obtained with M. tuberculosis Erdman in the same system (22). The fbpB mutant, LAb1, exhibited a similar growth curve.…”

“…Macrophage infections were carried out as previously described (21,22). Briefly, THP-1 cells were washed three times in the RPMI 1640 assay medium described above but with 2% AB serum, 1 g of tetrahydrobiopterin/ml, and no antibiotics.…”

“…The macrophage cell line culture method can be used to measure differences in capacity for intracellular growth among strains of mycobacteria (21,22). Human THP-1 macrophage cultures were infected with H37Rv and with the fbpA and fbpB mutants LAa1 and LAb1 to determine intracellular growth.…”

In Vitro Reversion of Amphotericin B Resistance in Leishmania donovani by Poloxamer 188

“…To check this hypothesis, the possibility of synergy between AmB and poloxamer 188 was studied with the promastigote form of the parasite. Synergism between nonionic surfactants (i.e., Triton WR139 or poloxamers CRL8131 and CRL8142) and antibiotics (isoniazide or clindamycin) against other intramacrophage pathogens such as Mycobacterium (14) or Toxoplasma gondii has already been reported (2). However, in all cases, these surfactants were more hydrophobic than the poloxamer 188 used in the present study.…”

Activities of Moxifloxacin Alone and in Combination with Other Antimicrobial Agents against Multidrug-Resistant Mycobacterium tuberculosis Infection in BALB/c Mice

“…The remaining mice were allocated either to untreated groups or to various drugtreated groups (six mice per group). The following drugs were administered by gavage five times weekly: ETH at 100 mg/kg (10), CS at 300 mg/kg (10), TC at 60 mg/kg (8), PAS at 750 mg/kg (17), and LNZ at 50 mg/kg (3). CM was administered subcutaneously at 150 mg/kg (10).…”