Microbiology. Weapons of microbial drug resistance abound in soil flora.

F ollowing the serendipitous discovery of penicillin in 1928 and streptomycin in 1943, the pharmaceutical industry has been screening thousands of soil samples for antimicrobial agents produced by inhabitant microbes. Chloramphenicol, clavulanic acid, erythromycin, gentamicin, rifampin, teicho-planin, tetracycline, and vancomycin represent only a few products of this spectacularly successful effort, and addition of these agents to the therapeutic arsenal has played a major role in controlling bacterial disease, the primary cause of human mortality in the preantibiotic era. The study by D'Costa et al. on page 374 this issue (1) provides a fascinating view of the flip side of this story. The authors isolated 480 morphologically diverse spore-forming microbes from the soil and tested these not as producers of antimicro-bial agents but rather as microbes that are resistant to existing antibiotics. Astonishingly, they found that every isolate was resistant to at least six to eight different antimicrobial agents and some to as many as 20! The antibiotics tested included both well-established and recently developed agents, natural products, semisynthetic derivatives, and fully synthetic antimicrobial agents. With multidrug-resistant bacterial pathogens spreading globally and the enormous efforts to trace the source and mechanism of spread of drug-resistant genes and clones (2), the study by D'Costa et al. has particular poignancy. It illuminates the dark side of the antibiotic paradigm: Microbes that synthesize the sophisticated chemicals that have been key to humankind's success in controlling bacterial disease also possess equally sophisticated mechanisms to protect themselves against their own toxic products. Lifted out of this context, these self-protecting mechanisms represent formidable weaponry that could annul the successes of antimicrobial therapy if they were to find their way into human pathogens. The microbes isolated and characterized by D'Costa et al. all belong to the genus Streptomyces, well known for producing multiple antimicrobial agents (3) that suppress the growth and/or kill other susceptible bacterial species in their vicinity. The 480 independent soil isolates examined presumably include producers of antimicrobial agents that also possess matching resistance mechanisms to protect against suicide in this chemical warfare (4). A number of the resistance mechanisms described by D'Costa et al. have not been previously characterized. Almost half of the test strains could enzymatically inactivate rifampin (often used against mycobacterial tuberculosis), in contrast to clinical isolates in which resistance is based on point mutations in a bacterial gene. Several strains could detoxify the semisynthetic drug telithromycin (for respiratory tract infections) by a …