Research Statement, Berthony Deslouches, MD, PhD
My long-term research goal is 2-fold: (1) to develop novel therapeutics primarily against hard-to-treat bacterial and viral infections; (2) to examine the impact of environmental factors on host defense with a focus on pathogenic bacterial exposure to toxicants.
- Antibiotics revolutionized medicine over the latter part of the last century. However, the rising rate of antibiotic resistance, the exorbitant costs of new drug development, and the complexities of obtaining FDA approval together threaten to erode the medical advances associated with the previous unprecedented successes of many different classes of antibiotics. The reduced enthusiasm for investing in basic antimicrobial research in most of the last forty years stalled further development of novel classes of antimicrobials although infectious diseases have remained among the top three global causes of death. Cationic antimicrobial peptides (AMPs), with membrane-perturbing selective mechanisms and rapid action against diverse types of pathogens, are an untapped resource with broad-spectrum activity paralleled by no other known group of agents to date. Attempts to develop AMPs for clinical application have largely failed due to a lack of understanding of structure-function relationship as these peptides are being engineered mostly through trial and error. To overcome the current limitations, it is necessary to establish a rational framework for successful AMP development, which can be accomplished by dissecting the amphipathic structure to titrate AMP structure-function properties of relevant groups (cationic vs. hydrophobic) of amino acids using a multidisciplinary approach. The development of this peptide antibiotic engineering technology will be the basis for the establishment of a robust and extramurally funded research program with enormous potential for multiple grant opportunities and long-term collaborations across multiple disciplines.
- Exposure to environmental toxicants is a serious health concern. Human populations exposed to environmental arsenic and tobacco smoke (ETS) have developed devastating diseases from cardiovascular disease to cancer. In addition, these toxicants enhance the susceptibility of the host to microbial pathogens. However, bacterial exposure to these environmental toxicants may also induce changes affecting virulence or resistance to treatment. Arsenic influences the gut microbiome composition toward more arginine-producing metabolites, suggesting a shift towards pathogenic bacteria in mice. However, the impact of these induced changes has not been fully investigated in relationship to the lung microbiota and susceptibility of the host to infections. Considering that arsenic incorporation in tobacco products from arsenic-endemic areas constitutes a higher risk of double exposure to smokers and those exposed to second-hand smoke, potential synergistic effects of arsenic/ETS need to be explored. Unpublished recent evidence in the lab demonstrates that arsenic/ETS-exposed aerugionsa displayed a higher propensity to adopt a biofilm mode of growth with a concomitant increase in gene expression consistent with upregulation of biofilm and virulence gene expression. It is, therefore, a long-term goal to investigate virulence- and drug resistance-related changes due to bacterial exposure to arsenic/ETS and the effects of these changes on pathogen interactions with exposed and nonexposed hosts in relationship with microbiome perturbations.
My research plan focuses on these two independent but interconnected objectives.