Inhibition of Pseudomonas aeruginosa by hyperbaric oxygen. I. Sulfonamide activity enhancement and reversal.
To elucidate an explanation for in vitro sulfonamide enhancement by high-pressure oxygen (HPO) and the reported absence of enhancement with in vivo therapy, Pseudomonas aeruginosa cultures were exposed to selected antifolate antimicrobials in the presence of 1.87 atm absolute of O(2) and compared with non-HPO treated controls. Under these conditions, HPO alone retarded growth. Trimethoprim, a non-sulfonamide which inhibits dihydrofolate reductase, was not bactericidal, nor did HPO enhance existent bacteriostatic activity. The sulfonamide, sulfisozazole, was not bactericidal, but HPO enhanced bacteriostatic activity twofold; bacteriostasis was mitigated in HPO-treated and control cultures by p-aminobenzoate but not by a mixture of compounds involved in folate-mediated "1-C" biosynthesis. Mafenide, a unique sulfonamide, at high concentrations with HPO, was synergistically bactericidal; non-HPO-treated cultures were bacteriostatically inhibited. Bacteriostatic activity of lower mafenide concentrations was also enhanced at least twofold by HPO. These inhibitory effects of mafenide, acting with or without HPO, were mitigated by the above mixture, but not by p-aminobenzoate. This may explain the lack of in vivo HPO-mafenide enhancement in burn-wound sepsis where exudates would contain such a mixture. Lastly, HPO itself was largely bactericidal at 2.87 atm absolute of O(2). This was reversed to various degrees by the above mixture, or its components, or by folic, folinic, or p-aminobenzoic acids. These in vitro interactions suggest HPO per se may act at the same site as some sulfonamides to inhibit folate synthesis (not primarily at the dihydrofolate reductase level), or coenzyme functions of folate, or both.
D062365:Aminobenzoates / Q000494:pharmacology; D004347:Drug Interactions; D005493:Folic Acid Antagonists / Q000494:pharmacology; D006931:Hyperbaric Oxygenation; D011312:Pressure; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000254:growth & development; D013444:Sulfisoxazole / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D014105:Tosyl Compounds / Q000494:pharmacology; D014295:Trimethoprim / Q000494:pharmacology
D062365:Aminobenzoates; D005493:Folic Acid Antagonists; D013449:Sulfonamides; D014105:Tosyl Compounds; D013444:Sulfisoxazole; D014295:Trimethoprim