Basic research and the challenges of microbiology for the 21st century.

Resistance to antibiotics has become a major concern for microbiologists, biochemists, and physicians worldwide. A report with the conclusions of a Workshop held at Rockefeller University in 1994 showed that several bacterial strains isolated from clinical specimens were resistant to all currently available antibiotics. This set off an alarm as to the dimensions of a possible environmental disaster if there were a diffusion of such human pathogens. These literally drug-immortal bacteria are a serious threat to human populations at the threshold of the 21st century. In 1996 WHO reported that the previous year 33% of the 52 million worldwide deaths were caused by infectious diseases. Since 1973, more than 30 emerging microorganisms (new infectious agents) have been identified. Examples of such new pathogens are: Legionella pneumophila , causing legionellosis; Cryptosporidium parvum, causing acute and chronic diarrhea; Vibrio choleraeO139, a new strain causing the recent cholera epidemic outbreaks; the human immunodeficiency virus (HIV); human herpes virus 8; Borrelia burgdorferi, causing Lyme disease; and the Ebola virus. Strong ecological pressures on our overpopulated planet and the free mobility of entire human populations have contributed to the emergence of new infectious diseases. The “resurrection” of bacterial pathogens is another major concern we have witnessed recently. Among reemerging bacteria are the causing agents of pneumonia (a group of bacteria that cause acute respiratory infections and are responsible for 4.4 million deaths per year), of tuberculosis (more than 3 million deaths per year), cholera, and yellow fever. In the United States, enterococci have become the third major nosocomial pathogen to produce endocarditis. By 1993, vancomycin, which had been an antibiotic used as a last resort against ultra-resistant bacterial strains, was already ineffective against many Enterococcus faecalisstrains. Similarly, Staphylococcus aureus strains resistant to methicillin rose from 8% in 1986 to 40% in 1992. Reemerging pathogens such as Neisseria meningitidis and Streptococcus pneumoniae have acquired new strategies for antibiotic resistance based on genetic exchange between different serotypes of certain virulence factors present in microorganisms. Such strategies comprise the formation of mosaic structures which alter the PBPs (penicillin-binding proteins) of the membrane or make it possible for the pathogen to escape the immunological protection acquired by vaccination. Characterization of the genes coding for the formation of the polysaccharide capsules that surround N. meningitidisshowed that they had been the cause of very virulent outbreaks of meningococcal meningitis detected in the states of Oregon and Washington in the late 1990s. A change from serotype b to serotype c had taken place. The people, who had been inoculated against serotype b, were defenseless against serotype c, and a major outbreak occurred. Epidemic outbreaks caused by S. pneumoniae , that originated from similar variations in the capsular types, had also been documented. The complexity of capsulated bacteria adds to the presence of antibiotic resistant g nes providing the bacteria with more weapons to develop epidemic outbreaks. Therefore, both ecological factors and the genetic characteristics of each pathogen play decisive roles in the emergence of infectious diseases. When penicillin started to be widely used in the mid-1940s, pneumococci were very sensitive to this antibiotic. It took some twenty years for the first resistant mutant to be isolated (1967, in Papua-New Guinea). The stabilization of genetic determinants of resistance is usually a long process, but once resistance is acquired, it spreads quickly. In the long run, strategies to defeat reemerging pathogens will have to involve a rational use of antimicrobial drugs as well as changes in social behavior, new public health regulations and information campaigns. Besides, in-depth knowledge of the specific mechanisms of resistance is essential to develop new antimicrobial agents. To acquire this knowledge, basic molecular and physiological research must look into the changes that infectious agents develop continuously in their natural habitats. The main step that must be taken to fight reemerging diseases is to develop basic microbiology. We must also Rubens López Ernesto García