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In this issue of the Journal of Bacteriology, Olesky et al. (13) report a novel observation regarding the mechanism by which Neisseria gonorrhoeae developed clinically significant levels of resistance to penicillin. Although yet to be fully defined, their results link changes in the structure of a gonococcal porin (PorB), which was presumed to modulate permeation of pen- icillin due to precedents set by studies with porins from Entero- bacteriaceae (1, 11), with overexpression of a multidrug efflux pump and the development of penicillin resistance in gono- cocci. The implications of their work for further advancing our knowledge regarding the structure-function relationships of the gram-negative cell envelope, differences between such bac- teria in this respect, and the connection of efflux pumps with other cell envelope proteins in the development of antibiotic resistance are substantial. Moreover, the findings justify con- tinued research on basic problems of antibiotic resistance even when the antibiotic in question is no longer used clinically to treat the disease in question. Historical review of chromosomally mediated penicillin re- sistance in gonococci. The introduction of antibiotics in gen- eral and penicillin specifically as a means to treat bacterial infections is arguably one of the greatest advances in modern medicine. Unfortunately, soon after its introduction, certain pathogens (e.g., Staphylococcus aureus) were noted to have quickly developed resistance to penicillin due to their produc- tion of penicillinase. Other infectious diseases, such as gonor- rhea, remained treatable with the relatively inexpensive peni- cillin G for several years. With respect to N. gonorrhoeae, strains expressing clinically significant levels of penicillin resis- tance emerged slowly. However, by the late 1960s and early 1970s, the peak of the gonorrhea epidemic in the United States, isolates were identified that displayed decreased sus- ceptibility to penicillin. Studies in the 1970s (6, 7, 16) and 1980s (2, 3, 17) showed that these strains contained chromosomally borne mutations that could additively increase resistance of gonococci to penicillin to a level approaching or at clinical significance (e.g., treatment failures). It is important to stress that these strains did not produce detectable penicillinase, although other (comparatively rare) strains bearing a plasmid encoding a TEM-1-type beta-lactamase were identified in the mid-1970s (15). With the report in 1985 (3) of a community-based outbreak of penicillin-resistant gonorrhea due to a strain not producing a beta-lactamase, the final blow to penicillin therapy for treat- ment of this sexually transmitted infection was, unfortunately, realized. The culprit strain (FA6140 (3)) from this outbreak contained (12) a number of chromosomal mutations (penA, penB, ponA, and mtr) that are known to alter cell envelope structure and/or function. In general terms, these mutations impact penicillin's accumulation in gonococci (penB and mtr) or affinity (penA and ponA) for penicillin-binding proteins; this commentary will be restricted to issues related to penB and mtr. The penB mutation was originally linked (7) to production of an altered major outer membrane protein (termed POMP or protein I) and was found to confer two- to fourfold increases in MIC levels of penicillin and tetracycline. Curiously, pheno- typic expression of penB required the presence of the mtr mutation, which was found to confer single-step resistance to structurally diverse hydrophobic antimicrobial agents (10) and was presumed to decrease cell envelope permeability to such agents (6).

journal of bacteriology

Towards an Understanding of Chromosomally Mediated Penicillin Resistance in <i>Neisseria gonorrhoeae</i> : Evidence for a Porin-Efflux Pump Collaboration

Towards an Understanding of Chromosomally Mediated Penicillin Resistance in Neisseria gonorrhoeae : Evidence for a Porin-Efflux Pump Collaboration