MRC National Institute for Medical Research, London
Science for Health
Luiz Pedro de Carvalho group project:
Rational antibiotic discovery and systems pharmacology
Understanding the mechanisms of action and resistance to antibiotics is key to their rational improvement, and to the development of strategies and molecules that can bypass resistance. We intend to apply modern metabolomic, proteomic, transcriptomic and chemical biological methods to define both pharmacodynamics and (intrabacterial) pharmacokinetics of antibiotics. Knowledge gained by these studies will rationally guide further improvements to the drugs (top in the figure).
Metabolomic analysis of intrabacterial pharmacology
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Top, structure of tizoxanide, the active component of nitazoxanide (Alinia®), an antimycobacterial drug candidate. Also shown is the use of global metabolomic profiling method to study its mechanism-of-action, generating a heat map that is clustered by the concentration of the drug and shows ~ 800 metabolites, some of which are affect by NTZ. Bottom, structure of nitazoxanide (NTZ) and tizoxanide (TIZ), which are candidate compounds for the treatment of tuberculosis.
The first antibiotic that we will study is nitazoxanide (NTZ), an attractive new lead compound for the development of anti-tuberculosis (TB) drugs. NTZ is a nitro-thiazolyl-containing pro-drug, which undergoes rapid deacetylation in the stomach, yielding tizoxanide (TIZ), which is believed to be the active species (bottom in the figure). Features that distinguish NTZ from other anti-TB candidates are its apparent lack of toxicity in humans, its ability to kill both replicating and nonreplicating Mycobacterium tuberculosis and its ability to evade resistance. Understanding the mechanism of NTZ action will guide the design of better analogs and help us understand the molecular determinants of NTZ’s unique action and possibly the molecular determinants of resistance bypass.
We are also in the process of obtaining a library of NTZ analogs and these compounds will be tested for killing of replicating and nonreplicating mycobacteria, resistance emergence and ability to kill Mtb in animal models of infection. Compounds that are active against both populations of Mtb and have ultra-low frequency of resistance are been intensily sought, as they could speed up treatment of TB and diminish the number of drugs required in the regimens.
In addition to NTZ, our lab is interested in the rational development of mechanism-based inhibitors for essential mycobacterial enzymes as well as enzymes involved in drug resistance in M. tuberculosis.
de Carvalho group
Recent publications
Research projects
- Functional genomics of mycobacterial enzymes
- Rational antibiotic discovery and systems pharmacology
- Metabolomics-level physiology studies
de Carvalho biography
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