Resistance to β-lactams in Mycobacterium fortuitum

It is widely assumed that the high level of intrinsic resistance to beta- lactam antibiotics exhibited by mycobacteria results from the combination of factors including permeability to the drugs, β-lactamase production, and affinity for penicillin-binding proteins (PBPs). We conducted an evaluation of the second and third factors by isolating nitrosoguanidine-induced mutants from the β-lactamase-producing strain Mycobacterium fortuitum ATCC 19542 that displayed either elevated or reduced resistance to various beta-lactam antibiotics. The mutants studied included D1 (a β-lactamase producer with high penicillin resistance), γ 27 (a low-level β-lactamase producer with low penicillin resistance), and D316 (a high-level β-lactamase producer with high penicillin resistance). In all strains examined, four major PBPs, named 1, 2a, 2b, and 3, with apparent molecular weights of 102,000, 90,000, 87,000, and 50,000, respectively, were found. The MICs of various beta-lactams toward ATCC 19542 and its mutants were considered in the context of β-lactamase production, the quantity of PBPs synthesized, and their affinities for beta- lactam antibiotics. The data obtained show that β-lactamase production is likely to be an important factor in the expression of resistance by clinical isolates and that PBP alterations can contribute to resistance at least in laboratory-derived mutants.