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.