M. Iqbal Choudhary and Atta-ur-Rahman, FRS


International Center for Chemical and Biological Sciences, (H. E. J. Research Institute of Chemistry and Dr. Panjwani Center for Molecular Medicine and Drug Research), University of Karachi, Karachi-75270, Pakistan

Abstract:

Anti-infection drug discovery and development is unfortunately receiving lesser attention and funding in global healthcare R&D. Many pharmaceutical conglomerates have either closed down or down-sized their anti-infection drug discovery programs. Similarly fewer researchers are engaged in academic institutions in this field. This is created an alarming situation which needs urgent action to avoid the menace of pre-antibiotic era. In this lecture, examples of our studies, focusing on the discovery of potential anti-infective leads will be presented.

Multidrug resistance (MDR) is a challenging problem for the healthcare sector. It is very common in most important pathogens, such as vancomycin-resistant Enterococci and Staphylococcus aureus. Exposure and inappropriate use of the antibiotics is the major cause of MDR, both in developed and developing regions. We have been focusing our efforts on the discovery of natural and synthetic compounds, active against MDR bacteria Staphylococcus aureus and Pseudomonas aeruginosa (resistant to over 20 antibiotics). About1400 fully characterized natural and synthetic compounds were evaluated by high throughput screens against MDR S. aureus and P. aeruginosa (NCTC strains and various clinical isolates were used for comparative studies). We have discovered some potent, reproducible and highly active MDR inhibitors of flavonoids, monoterpenes, sesquiterpenes, quinolones, thiourea derivatives and organometallic. Mechanism-based studies on selected compounds of both synthetic and natural origin were also carried out to assess the compound-induced effect on membrane potential, efflux pump inhibition, etc. Biochemical and enzymatic alteration on ultra structure defects in cells also evaluated out by transmission and scanning electron microscopy. In addition to this, we also studied the cell damage by superoxide, produced by selective natural and synthetic compounds, and the reversal of multidrug resistance by using the MDR inhibitors which boost the antimicrobial activity of antibiotics by improving their penetration into the bacterial cells.

Leishmaniasis is caused by protozoal parasites of the genus Leishmania, a biologically diverse group of flagellate parasites. Leishmaniasis is endamic in tropical and subtropical regions, such as south and east Africa, Afghanistan, Iran, China, Nepal, Brazil, Bangladesh, etc. Based on the high prevalence of leishmaniasis in our region and associated morbidity, we conducted a systemic study on folk medicines used against leishmaniasis in Pakistan. We have isolated antileishmanial agents of natural origin and conducted in vitro screening as well as animal toxicity assays. We also conducted human clinical trials on leishmaniasis patients by applying topical applications of new ointment based formulations. A total of 110 patients were recruited with clinical leishmaniasis, diagnosed by smear examination on lesions. The results of this clinical study unambiguously established the efficacy, safety and cost effectiveness of the Physalis minima extracts-based topical gel.