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In many developing countries and outside hospital settings, the characteristics of endemic Mycobacterium tuberculosis strains resistant to multiple drugs remain unknown. In a community-based referral and therapy program in northern Lima, Peru, beginning in 1996, patients found to be failures on standard regimens were referred for drug-susceptibility testing of their isolates, and those found to be infected with M. tuberculosis isolates resistant to at least rifampin were treated with individualized regimens based on their infecting strains. Isolates from 42 of these patients were subjected to DNA sequencing of the rpoB gene region responsible for rifampin resistance. We determined the frequency of types of mutations in the rpoB gene among these Peruvian isolates.

Uncoupler resistance presents a potential challenge to the conventional chemiosmotic coupling mechanism. In E. coli, an adaptive response to uncouplers was found in cell growing under conditions requiring oxidative phosphorylation. It is suggested that uncoupler-resistant mutants described in the earlier literature might represent a constitutive state of expression of this "low energy shock" adaptive response. In the environment, bacteria are confronted by nonclassical uncoupling factors such as organic solvents, heat, and extremes of pH. It is suggested that the low energy shock response will aid the cell in coping with the effects of natural uncoupling factors. The genetic analysis of uncoupler resistance has only recently began, and is yielding interesting and largely unexpected results. In Bacillus subtilis, a mutation in fatty acid desaturase causes an increased content of saturated fatty acids in the membrane and increased uncoupler resistance. The protonophoric efficiency of uncouplers remains unchanged in the mutants, inviting nonorthodox interpretations of the mechanism of resistance. In E. coli, two loci conferring resistance to CCCP and TSA were cloned and were found to encode multidrug resistance pumps. Resistance to one of the uncouplers, TTFB, remained unchanged in strains mutated for the MDRs, suggesting a resistance mechanism different from uncoupler extrusion.

E. coli adapt to uncouplers in the presence of a non-fermentable carbon source. Adaptation is accompanied by the restoration of the proton motive force and ATP. A collection of uncoupler-sensitive Tn,lacZ,kan fusion strains was obtained by ampicillin enrichment in the presence of TSA. One of the fusion strains was induced by uncouplers. The fusion gene emrD was mapped to min. 83.1, cloned and sequenced. EmrD is a member of the major facilitator family of pmf-dependent translocases and is homologous to a number of bacterial multidrug resistance pumps. Resistance to some uncouplers including TTFB was not affected by emrD, and growth recovery to this uncoupler was very sluggish. It is suggested that EmrD is a new bacterial multidrug resistance pump that participates in a low energy shock adaptive response.