Importance of secondary screening with clinical isolates for anti-leishmania drug discovery

Abstract

The growing drug resistance (DR) raises major concerns for the control of visceral leishmaniasis (VL), a neglected disease lethal in 95 percent of the cases if left untreated. Resistance has rendered antimonials (SSG) obsolete in the Indian Sub-Continent (ISC) and the first miltefosine-resistant Leishmania donovani were isolated. New chemotherapeutic options are needed and novel compounds are being identified by high-throughput screening (HTS). HTS is generally performed with old laboratory strains such as LdBOB and we aimed here to validate the activity of selected compounds against recent clinical isolates. In this academic/industrial collaboration, 130 compounds from the GSK “Leishbox” were screened against one SSG-sensitive and one SSG-resistant strain of L. donovani recently isolated from ISC patients, using an intracellular assay of L. donovani-infected THP1-derived macrophages. We showed that only 45% of the compounds were active in both clinical isolates and LdBOB. There were also different compound efficiencies linked to the SSG susceptibility background of the strains. In addition, our results suggested that the differential susceptibility profiles were chemical series-dependent. In conclusion, we demonstrate the potential value of including clinical isolates (as well as resistant strains) in the HTS progression cascade.

Characterization of Antimicrobial, Antioxidant, and Leishmanicidal Activities of Schiff Base Derivatives of 4-Aminoantipyrine

“…Schiff bases are an emerging alternative for disease treatments. In the last decades, many types of resistance have been described in bacteria, generating the need for new drugs for dealing with the diseases caused by microbes [3,4]. In addition, the prevalence of cancer and metabolic diseases such as diabetes are predicted to rapidly grow in the next years [51,52].…”

“…In the last decades, antibiotic resistances have been described in several microorganisms, including those having multiresistance phenotypes [1,2,3,4]. This is an alarming situation, as noted by the World Health Organization, and many researchers have focused on the development of new therapeutic alternatives.…”

Discovery of novel hit compounds with broad activity against visceral and cutaneous Leishmania species by comparative phenotypic screening

“…amazonensis , an observation that is reminiscent to previous studies showing species-specific susceptibility to various reference drugs 42 . In this context, recent data by Hefnawy and colleagues showed the importance to also consider clinical isolates in secondary screens as they revealed different susceptibility profiles to Leish-Box compounds 43 . Less than 50% of the compounds active on LdBOB showed activity against the field isolates.…”

Of Drugs and Trypanosomatids: New Tools and Knowledge to Reduce Bottlenecks in Drug Discovery

“…Markedly, and despite their many advantages, engineered parasites are not flawless, and different mitigation strategies should be taken into account in order to avoid any compensatory change in parasite metabolism or virulence (e.g., prioritize the use of integrative strategies to generate the strain) [ 35 ]. A final important remark is that, as has been recently demonstrated, there could be different compound efficiencies linked to the drug susceptibility background of the Leishmania strains used in the screening process (especially in the case of antimony susceptibility), which shows the potential value of including clinical isolates (and resistant strains) in the drug discovery cascade [ 47 ].…”