Associate Professor Pablo Bifani

Research Interest

Antimicrobial resistance (AMR) is one of the largest public health issues facing of the 21st century and greatly impedes infectious disease control. The primary interest of our laboratory is to understand the mechanisms of drug resistance in three different organisms: Mycobacterium tuberculosis, Enterobacteriaceae and the Plasmodium malaria parasite. Tuberculosis (TB) and malaria contribute heavily to the global infectious disease burden and are leading cause of morbidity and mortality. Mycobacterium tuberculosis, the etiological agent of TB, was responsible for 10.4 million new cases, 1.8 million deaths and 580,000 cases of multidrug-resistant or rifampicin-resistant TB in 2015 (WHO report 2017). Malaria is a parasitic disease caused primarily by the Plasmodium falciparum and Plasmodium vivax in humans, accounting for 212 million new cases and 429 000 malaria deaths in 2015 (WHO Malaria report). While recent malaria control programs have been recognized for a 21% decrease in incidence between 2010 and 2015, emerging resistance to artemisinin-based combination therapies (ACTs) threaten to thwart malaria eradication initiative. In contrast to the pathogenic properties of TB and malaria, Klebsiella pneumoniae is an opportunistic pathogen that can be asymptomatic colonizers of the human gastrointestinal tract, respiratory tract, nasopharynx, oropharynx, and skin. It afflicts primarily the neonates, elderly and immunocompromised. In the last decade multidrug resistant K. pneumonia has emerged as a major global public health problem and is a prominent member of the notorious ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.), a group of multidrug resistant pathogens responsible for the majority of hospital-acquired infections.

The identification of the mechanisms of antimicrobial resistance can have several impacts in drug discovery, diagnostics and infection control. These includes providing molecular information pertaining to the frequency of resistance to a given drug, facilitating the development of analogs active against the resistant strains, and identifying targets for the development of reliable molecular diagnostic tools to track down resistant strains in the clinical settings. Understanding the targets and mechanisms of resistance provides a guideline for effective combination therapy.

Current projects

• Understanding mechanisms of resistance and action of antituberculars
• Bacterial fitness of rifampicin resistant TB
• Developing models to study drug resistance and virulence in Klebsiella pneumoniae
• Establishing a model to study antimalarials and drug discovery using the simian malaria parasite Plasmodium cynomolgi as a surrogate for Plasmodium vivax

Recent Publications

1. Voorberg-van der Wel A., et. al., (2017) A comparative transcriptomic analysis of replicating and dormant liver stages of the relapsing malaria parasite Plasmodium cynomolgi. Elife, 2017 7;6. pii: e29605. doi: 10.7554/eLife.29605.
2. Kosaisavee V., et. al., (2017) Species-specific Tropism for Erythrocyte Invasion as an Impediment to Plasmodium cynomolgi’s Zoonotic Potential. Blood- 11. pii: blood-2017-02-764787.
3. Dembele L., et. al., (2017) The Plasmodium PI(4)K inhibitor KDU691 selectively inhibits dihydroartemisinin-pretreated Plasmodium falciparum ring-stage parasites. Sci Rep. 2017 May 24;7(1):2325.
4. Lim, M., et. al., (2016) UDP-galactose and Acetyl-CoA transporters as Plasmodium multidrug resistance genes. Nature Microbiology, 1:161-66.
5. LaMonte, G., et. al., (2016) Mutations in the P. falciparum Cyclic Amine Resistance Locus (PfCARL) confer multi-drug resistance. mBio 7, e00696-00616.
6. Haver, H. L., et. al., (2015) Mutations in genes for the F420 biosynthetic pathway and a nitroreductase enzyme are the primary resistance determinants in spontaneous in vitro-selected PA-824-resistant mutants of Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy, 59, 5316-5323.
7. Yokokawa, F., et. al., (2013) Discovery of tetrahydropyrazolopyrimidine carboxamide derivatives as potent and orally active antitubercular agents. ACS Medicinal Chemistry Letters 4, 451-455
8. Rao, S. P., et. al., (2013) Indolcarboxamide is a preclinical candidate for treating multidrug-resistant tuberculosis. Science Translational Medicine 5, 214ra168.
9. Pethe*, K., et. al., (2013) Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis. Nature Medicine 19, 1157-1160.
10. Stoffels, K., et. al., (2012) Systematic analysis of pyrazinamide-resistant spontaneous mutants and clinical isolates of Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy 56, 5186-5193.
11. Willand, N., et. al., (2009) Synthetic EthR inhibitors boost antituberculous activity of ethionamide. Nature Medicine 15, 537-544.
12. Mathys, V., et. al., (2009) Molecular genetics of para-aminosalicylic acid resistance in clinical isolates and spontaneous mutants of Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy 53, 2100-2109

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