Title : Sensitivity of antimony(III)-sensitive and -resistant MRPA-overexpressing and AQP1-mutated Leishmania strains towards novel organoantimony(V) and organobismuth(V) complexes and their effect on DNA and membrane integrity

Abstract:

Aim: To investigate the effect of novel organometallic Sb(V) and Bi(V) complexes on membrane integrity and their interaction with DNA, activity and cytotoxicity against Sb(III)-sensitive and -resistant Leishmania strains.

Material & Methods: Ph₃M(L)₂ type complexes were synthesized, where M= Sb(V) or Bi(V) and L= deprotonated 3-(dimethylamino)benzoic acid (HL1) or 2-acetylbenzoic acid (HL2).

Results: Both organobismuth(V) and organoantimony(V) complexes were found to be efficient at micromolar concentrations against Leishmania amazonensis and L. infantum but only the later ones remained biocompatible. Ph₃Sb(L1)₂ and Ph₃Bi(L1)₂ showed no cross-resistance with inorganic Sb(III)-resistant MRPA-overexpressing L. amazonensis and AQP1-mutated L. guyanensis and could permeate cell membrane and interact with the Leishmania DNA, suggesting that this effect may contribute to the parasite growth inhibition via apoptosis.

Conclusion: Our data taken altogether support the model of different mechanism of action and uptake pathway in Leishmania for these organometallic complexes, when compared to the conventional inorganic antimonial drugs.

Keywords: Leishmaniasis; organometallics; antimony and bismuth; drug resistance; mechanism of action; membrane permeability and DNA interaction.

Audience Take Away: 

• The audience will learn about novel organometallic Sb(V) and Bi(V) complexes as promising antileishmanial agents. These complexes show effectiveness against both Sb(III)-sensitive and -resistant strains, offering potential solutions for treatment-resistant cases.
• The presentation sheds light on the potential mechanisms behind the complexes' effectiveness. Studies suggest membrane permeability and DNA interaction as key factors, differing from the action of conventional antimony drugs.
• Understanding the distinct mechanisms of these complexes can guide researchers in designing new antileishmanial drugs with different targets and potentially overcome resistance.
• The research provides valuable insights for researchers studying drug resistance and parasite biology in Leishmania. New lines of investigation can be explored based on the observed interactions with cell membranes and DNA.
• The biocompatibility and efficacy of these complexes, particularly the organoantimony(V) ones, highlight their potential for further development into therapeutic options for leishmaniasis treatment.
• Faculty Research Expansion: Provides a new class of antileishmanial agents with distinct mechanisms for researchers to investigate and potentially collaborate on.
• Drug Design and Development: Offers valuable insights into alternative targets and strategies for designing new drugs or optimizing existing ones.
• Improving Diagnostic Accuracy: Understanding the interaction with membranes and DNA may contribute to developing new diagnostic tools for leishmaniasis.

Biography:

Driven by a passion for combating disease, Dr. Arshad Islam brings his expertise in metal-based drug design to the medical field. With a PhD in Biological Chemistry and postdoctoral experience in Physiology, Pharmacology and immunopathology, his research focuses on developing potent and effective therapies for leishmaniasis, Chagas disease, infections, and even cancer.

Dr. Islam's work delves into the intricate dance between metals and molecules, creating innovative organometallic and nanoscale drug delivery systems. His research, encompassing both lab and animal models, seeks to unlock the mysteries of disease biology and pave the way for improved treatments. With over 25 publications in prestigious journals and 7 book chapters, his dedication to sharing knowledge illuminates the path for future scientific advancements.

Committed to making a global impact, Dr. Islam's journey from international fellowships to his current role as an Assistant Professor and Consultant in Pakistan exemplifies his unwavering dedication to improving healthcare, one molecule at a time.