Combating Drug Resistance with Basic Research
NIAID has invested considerable resources into basic research that aims to understand the make-up and behavior of microbes and how drug resistance develops. Understanding precisely how microbes cause disease (the process called pathogenesis) is also crucial for finding new ways to combat them.
Insights into Mechanisms of Resistance
Basic research aims to understand the fundamental biology of pathogenic microbes and provides insight into the mechanisms used by microbes to block antimicrobial drugs. This knowledge generates new ideas for ways to get around these mechanisms, by restoring efficacy to existing drugs or by identifying new antimicrobial drug targets for the design of new antimicrobials. For example, when NIAID grantees determined the structure and genetic underpinnings of a “pump” that bacteria use to rid themselves of the antibiotic tetracycline, scientists could begin designing new compounds that could block the bacterial pump, thus allowing tetracycline to enter the bacterial cell and cure infection. Experimental drugs to block the pump are now being tested in animals.
How Pathogens Cause Disease
Microbial pathogenesis is another focus of basic research that studies how microbes cause disease, including how they colonize and invade the host, the toxins they produce, and how they avoid or overcome an attack by the host’s immune defenses. Basic research by NIAID scientists is revealing new details about microbial pathogenesis. For example, investigators have identified bacterial proteins produced by community-associated MRSA (CA-MRSA) that destroy infection-fighting white blood cells. A better understanding of the role these proteins play in creating the conditions for severe CA-MRSA infections could lead to new ways to treat or prevent the illness.
Deciphering Microbial Genomes
New pathways towards understanding drug resistance are revealed when scientists determine the sequence of genes that make up a microbe’s genome. Genetic analysis can also reveal vulnerable areas in a microbe’s genome that could be potential drug targets, or this information could aid in the development of better diagnostic tests. By isolating the same species of microbe from different geographic locations or from different human populations and comparing their genetic information, we may be able to identify when and where resistance first emerged in these species, as well as identify what mechanisms of resistance they are using.
- Recognizing the importance of microbial genomic research, NIAID has supported genomic sequencing through its Microbial Sequencing Centers since 1998. Researchers at these centers have sequenced the genomes of more than 40 disease-causing bacteria and numerous viruses, parasites, and fungi. Examples include bacteria that cause extensively drug-resistant tuberculosis; several species of Staphylococcus; and several species of Streptococcus bacteria, including one that causes so-called flesh-eating disease.
- A research resource dedicated to understanding Staphylococcus aureus draws together more than 200 investigators, clinical lab scientists, and epidemiologists who share information and maintain a repository of over two hundred S. aureus strains. The NIAID-supported repository (non-government link) helps researchers keep tabs on the emergence of new drug-resistant strains of S. aureus.
Computer-Assisted Modeling Efforts
With genomic information available, NIAID-supported researchers are using computer modeling techniques to create artificial metabolic pathways for individual microbes that reveal clues about possible targets for new antimicrobial drugs. Virtual representations of potential drugs are first built by computer. Only the most promising of these virtual compounds are synthesized in the lab and tested for antimicrobial activity. This time- and money-saving method allows many compounds to be judged quickly for their potential usefulness.
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