Diseases caused by bacteria from the genus Mycobacterium have afflicted humankind for millennia and currently represent a significant source of mortality and morbidity. Examples are human tuberculosis, leprosy, Buruli ulcer, and other soft-tissue and lung infections. Tuberculosis alone is still responsible for 1.5 million deaths annually. The increased prevalence of antibiotic resistance in mycobacteria is a significant problem, causing nearly untreatable infections.
The Carvalho Lab is interested in defining how soil-dwelling and water-borne mycobacteria became adapted to the human host, a prerequisite for a human pathogen. Our group focuses particularly on understanding how mycobacterial metabolism and chemistry evolved in the last 50 to 150 million years, to allow for optimal growth and virulence in humans. Once these processes have been mapped and characterized at cellular and molecular levels, we will create state-of-the-art methods, some of which have been pioneered at The Wertheim UF Scripps Institute, to discover and develop novel small molecules capable of killing these pathogens and transform the therapy of tuberculosis and other mycobacterial diseases.
Our research is anchored in four foundational pillars: discovering metabolites (right), linking them to enzymes (top), mapping their integration into metabolic pathways (left), and elucidating mechanisms that inform on biologically and pharmacologically relevant phenotypes (bottom).
Recent key advances include:
- Discovery of the first example of target-mediated antibiotic inactivation
- Identification of the metabolic requirements for pyruvate and lactate utilization by M. tuberculosis
- Discovery of itaconate catabolism in M. tuberculosis and its intersection with amino acid metabolism
- The first fine mapping of nitrogen metabolism in M. tuberculosis
- Demonstration of the crucial role of metabolism in bacterial L-form
- Discovery of the first NAD+ phosphorylase and its role in M. tuberculosis cell death
- Reveal that phosphate-less composition of the plasma membrane of M. tuberculosis
- Reveal of a disconnect between antibiotic resistance and known resistance determinants in mycobacteria
- Discovery of a pathway to degrade host-derived itaconate in M. tuberculosis, conferring resistance to it