The Saban Research Institute
Childrens Hospital Los Angeles
Research TopicsMicrobial/Invertebrate Genetics, Evolutionary Biology, Drug Design, Delivery, Gene Regulation/Transcription
Research OverviewDrug Resistance in Mycobacteria
The main research interest in my laboratory is the study of the emergence of antibiotic/antimicrobial resistance in mycobacteria, especially Mycobacterium tuberculosis (the causative agent of tuberculosis) and M. avium. Tuberculosis is still one of the most important single causes of preventable death worldwide, killing over 3 million people each year. This number of deaths is more than caused by all forms of cancer combined. Furthermore, each year there are approximately 9 million new cases of symptomatic tuberculosis. However, this incidence is dwarfed by the estimate that 500 million people are or have been infected with the tubercle bacillus, with possibly 50 million infected with drug resistant organisms.
There are effective treatments for tuberculosis, usually comprising 4 or 5 antimicrobial agents, including isoniazid (INH), rifampin (RIF), pyrazinamide (PZA) and either ethambutol (EMB) or streptomycin (STR). However, the treatment course lasts for several months, which can lead patient non-compliance and treatment inconsistency. These, and other problems (e.g. inappropriate therapy), increase the risk of drug resistance emerging especially in patients also infected with HIV. In the United States, resistance to one of the primary treatment agents (INH, RIF, PZA, EMB or STR) is expressed by 10 - 15% of M. tuberculosis isolates.
The mutational bases of antimicrobial resistance in mycobacteria have been largely characterized. We were instrumental in describing the mutations associated with macrolide (e.g. clarithromycin) resistance and also in describing novel mutations associated with rifampin resistance. Despite this knowledge, there is little information on the mutation process, nor what factors influence the emergence of resistance at the level of the individual bacterium. We have found that the mutations that confer antimicrobial resistance are not spontaneous events, but appear to be dependent on the presence and concentration of the drug. Furthermore, we have found that resistant organisms derive from progenitors that appear to be in an uncommitted genetic state. Thus, we hypothesize the molecular and genetic state of the bacilli prior to the presence of antimicrobial agent is important to the acquisition of resistance associated mutations. We are currently testing this hypothesis by studying resistance-associated mutagenesis at the molecular level.
As well as an interest in mycobacteria, we are also studying antimicrobial resistance in other bacteria, particularly species of the genus, Corynebacterium. There is recent data suggesting that corynebacteria may be important environmental reservoirs of drug (e.g. macrolide) resistance. We have characterized the molecular basis of macrolide resistance in the opportunistic pathogen, C. jeikeium. This organism is of interest clinically because it is a commonly found colonizing the skin of long-term hospitalized patients, especially those with cancer.
The study of antimicrobial resistance will lead to the design and implementation of more effective treatment regimens, and also the design of new approaches to preventing the emergence of resistance.