Effect of poloxamer CRL-1072 on drug uptake and nitric-oxide-mediated killing of Mycobacterium avium by macrophages

Mycobacterium, avium-intracellulare complex (MAI) are common pathogens of o pportunistic infections that are naturally resistant to most antibiotics an d develop acquired resistance rapidly. An experimental drug, poloxamer CRL- 1072, was found to have two unusual properties it synergistically enhanced the activity of several antibiotics against MAI even though it had little a ctivity as a single agent and it had greater activity against MAI in macrop hage culture or in mice than in broth culture. Studies were undertaken to i nvestigate the mechanisms of these effects, CRL-1072 was taken up by MAI an d enhanced the uptake of fluorescent-labeled streptomycin and erythromycin in broth culture, The labeled antibiotics had reduced activity so the relev ance for naive antibiotics must be inferred. In culture with human U937 mon ocytoid cells, CRL-1072 became localized in phagosomes acid promoted uptake of streptomycin. Finally, CRL-1072 was found to induce production of mRNA for inducible nitric oxide synthase (iNOS) and nitric oxide (NO) by U937 ce lls, The antimycobacterial effect in macrophages was reversed by the iNOS i nhibitor N-monomethyl L-arginine (NMMA), suggesting that CRL-1072 promotes killing of MAI by inducing NO. These effects were induced by noncytotoxic c oncentrations of CRL-1072, These data suggest that the antimycobacterial me chanisms of CRL-1072 include enhancing the delivery of antibiotic to target s within MAI and enhancement of the ability of macrophages to kill ingested organisms. (C) 2000 Elsevier Science B.V, All rights reserved.