Infectious tropical diseases such as malaria and tuberculosis are a growing public health threat in Thailand owing to the emergence and spread of drug-resistant pathogens. In response to this need, the Medical Molecular Biology Research Unit engages in multi-disciplinary research activities towards the goal of developing new medicines effective against the drug-resistant pathogens.  The approach revolves mainly around gene and protein engineering, structural biology, drug design and synthesis.

Research Scope

  • Malaria Research. The main goal of malaria research is rational development of novel antimalarial drugs that can overcome drug resistant malaria parasites. The research targets enzymes in the folate metabolism pathway, particularly the two enzymes already validated as drug targets for malaria, namely dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS). Multi-disciplinary approaches are used to rationally design and synthesize new compounds effective against currently drug-resistant parasites. The approaches used include X-ray crystallography and molecular modelling to understand drug-ligand binding at the molecular level and for aiding drug design, medicinal chemistry to synthesize novel compounds, and development of transgenic parasite lines to validate targets and to use as screening platforms for drug discovery.
  • Tuberculosis Research. Tuberculosis research is focused on drug target identification and development of screening assays, study of drug resistance mechanisms and development of rapid diagnostic methods for TB and drug-resistant TB including assays for latent TB infection. In addition, epidemiological studies among Mycobacterium tuberculosis transmitted in Thailand and host-pathogen interactions are also research fields of importance and interest.

List of Laboratories

Highlights

  • A library of more than 1,000 antifolate compounds have been designed, synthesized, and screened, several of which demonstrate highly potent antimalarial activity.
  • One candidate “P218”, which is highly effective against drug-resistant malaria in both in vitro and in vivo assays and demonstrated good drug-like properties, and is now undergoing preclinical studies for proof-of-human-use in collaboration with Medicines for Malaria Venture (MMV), a non-profit organization in Switzerland.
  • Development of in vivo and in vitro screening models for determining inhibitory effects of new antifolate compounds:Use of surrogate bacteria and parasite models developed to predict new resistant mutants against antifolate compounds in order to pre-circumvent future mutants.
    • Screening of antifolate compounds using in vitro culture of laboratory-adapted sensitive and resistant Plasmodium falciparum strain.
    • In vitro screening of antifolates using transgenic Plasmodium falciparum parasites expressing Plasmodium vivax dhfr genes (surrogate Plasmodium vivax malaria model)
    • Use of transgenic parasites expressing green fluorescent protein (GFP) for rapid screening of antimalarial compounds.
    • In vitrobacterial surrogate models in which the dhfr and/or dhps genes were replaced with the respective homologues from malaria parasites
    • In vivoscreening of antifolates using transgenic rodent malaria (Plasmodium berghei) whose nativedhfrgene had been replaced with the homologous gene from either Plasmodium falciparum or Plasmodium vivax (surrogate human malaria model forin vivo drug testing).
  • Determination of crystal structures and enzyme kinetic properties of drug targets such as dihydrofolate reductase-thymidylate synthase (DHFR-TS) of malaria, Trypanosomes and Toxoplasma, DHPS and serine-hydroxy methyl transferase (SHMT) of malaria parasite and fructose-1,6-bisphosphate aldolase enzyme of M. tuberculosis.
  • Development of a new inducible riboswitch reverse-genetic system for specifically attenuating gene expression in Plasmodium falciparum; new drug targets validated by this method include parasite genes essential for protein export and host cell remodelling.
  • Discovery of two novel genes Rv2136c and ksgA involved in intrinsic clarithromycin resistance in M. tuberculosis.
  • Discovery of M. tuberculosis VNTR as a biomarker for genotyping of M. tuberculosis strains.
  • Production of purified recombinant protein MPT64 to replace PPD (purified protein derivative) in PPD skin test.
  • Rapid methods for detection of TB and multi-drug resistant (MDR)-TB.

Major Equipment and Facilities

  • Molecular biology and drug screening facility
  • Single crystal X-ray diffraction system
  • Flow cytometry system
  • Liquid chromatography-tandem mass spectrometer (LC-MS/MS)
  • Fluorescence microscope
  • Laser scanning confocal microscope
  • Isothermal titration calorimetry

Director

Dr. Sumalee Kamchonwongpaisan

Contact Address

Medical Molecular Biology Research Unit
National Center for Genetic Engineering and Biotechnology (BIOTEC)
113 Thailand Science Park
Phahonyothin Road, Khlong Nueng, Khlong Luang
Pathum Thani 12120, Thailand
Tel: +66 (0) 2564 6700
Fax: +66 (0) 2564 6707
Website: http://www.biotec.or.th/mmu