Relationship of thiol structures to reaction with antibiotics.

A large number of the antibiotics have demonstrated chemical reactivity toward compounds containing sulfhydryl groups (1, 2). There have also been observed marked differences in reactivity of individual antibiotics toward various types of sulfhydryl-containing compounds. In the present investigation, the effect of structure of thiol compounds on their ability to react with certain antibacterial agents is interpreted in terms of the possible relationship of structure of thiol groups in proteins with factors of specificity and degree of activity of antibiotics. The importance of sulfhydryl groups to enzyme activity has been demonstrated frequently (3-9), although the exact functions of the group are still in doubt. The antibiotics studied were penicillin G, streptomycin, gliotoxin, pyocyanine, and the active principles of B&urn sativum (CsH&O), Arcfium minus (C&H200rJ, and Asarum canadense (principle A) (10). This is a chemically heterogeneous group with examples of antibiotics derived from bacteria, molds, Actinomyces, and higher plants, but all react with certain sulfhydryl compounds. Some of these antibiotics previously (2) were discussed briefly with respect to inactivation by a number of thiols and it was postulated that this class of antibacterial agents acted by combining with essential sulfhydryl groups of enzymes and that probable factors involved were diffusibility of the antibiotic throughout the microbial cell structure, degree of adsorption of the antibiotic by enzymes, and ability of the antibiotic to react with sulfhydryl groups of the enzymes. Penicillin has shown a high degree of specificity in its reaction with thiols. Cysteine, its esters, and p-aminoand ,8-dimethylaminoethanethiols are good penicillin inactivators; homocysteine, N-acetylcysteine, and thioglycolate are poor (2). Cysteine and aminoethanet.hiol are equally effective ; however, dl-/?, P-dimethylcysteine (dl-penicillamine) (11) is not effective, showing interference from P-carbon substituents other than hydrogen. On the basis of present information the ideal thiol type of inactivator for penicillin should possess a basic amino group (primary through tertiary) on the carbon adjacent to the carbon carrying the sulfhydryl group, with substituents on the nitrogen smaller than ethyl (methyl or hydrogen). When using this information in predicting the possible