Mirincamycin, an old candidate for malaria combination treatment and prophylaxis in the 21st century: in vitro interaction profiles with potential partner drugs in continuous culture and field isolates

Malaria Journal

Research

Wolfgang Graninger¹  Deepa Ganesh²  Paul Swoboda³  Harald Noedl³  Peter Starzengruber⁴  Hans-Peter Fuehrer⁵  Rashidul Haque⁶  Wasif A Khan⁶ 

[1] Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria;Institute of Medical Chemistry, Department of Biochemistry and Genetics, Medical University of Vienna, Vienna, Austria;Institute of Specific Prophylaxis and Tropical Medicine, Medical University of Vienna, Vienna, Austria;MARIB, Malaria Research Initiative Bandarban, Bandarban, Bangladesh;Institute of Specific Prophylaxis and Tropical Medicine, Medical University of Vienna, Vienna, Austria;MARIB, Malaria Research Initiative Bandarban, Bandarban, Bangladesh;Department of Hospital Hygiene and Infection Control, Vienna General Hospital, Medical University Vienna, Vienna, Austria;Institute of Specific Prophylaxis and Tropical Medicine, Medical University of Vienna, Vienna, Austria;MARIB, Malaria Research Initiative Bandarban, Bandarban, Bangladesh;Department of Pathobiology, Institute of Parasitology, University of Veterinary Medicine Vienna, Vienna, Austria;International Centre for Diarrhoeal Disease Research, Bangladesh, Dhaka, Bangladesh;

关键词: Mirincamycin;    In vitro;    Malaria;    Interaction profile;    Plasmodium falciparum;    Resistance;    Tafenoquine;    Chloroquine;   

DOI  :  10.1186/1475-2875-13-228

 received in 2014-02-28, accepted in 2014-05-30,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundSpreading resistance of Plasmodium falciparum to existing drugs calls for the search for novel anti-malarial drugs and combinations for the treatment of falciparum malaria.MethodsIn vitro and ex vivo investigations were conducted with fresh P. falciparum field isolates and culture-adapted P. falciparum clones to evaluate the anti-malarial potential of mirincamycin, a lincosamide, alone and in combination with tafenoquine (TQ), dihydroartemisinin (DHA), and chloroquine (CQ). All samples were tested in a histidine-rich protein 2 (HRP2) drug susceptibility assay.ResultsInteraction analysis showed additive to synergistic interaction profiles with these potential partner drugs, with an overall geometric mean fractional inhibitory concentration at 50% inhibition (FIC50) of 0.78, 0.80 and 0.80 for mirincamycin with TQ, DHA, and CQ, respectively. Antagonism was not found in any of the tested field isolates or clones. The strongest tendency toward synergy (i.e. the lowest FIC) was seen with a combination ratio of 1:0.27 to 1:7.2 (mean 1:2.7) for the combination with tafenoquine. The optimal combination ratios for DHA and CQ were 1:444.4 to 1:36,000 (mean 1:10,755.5) and 1:2.7 to 1:216 (mean 1:64.5), respectively. No evidence of an activity correlation (i.e. potential cross-resistance) with DHA, mefloquine, quinine or chloroquine was seen whereas a significant correlation with the activity of clindamycin and azithromycin was detected.ConclusionsMirincamycin combinations may be promising candidates for further clinical investigations in the therapy and prophylaxis of multidrug-resistant falciparum malaria or in combination with 4 or 8-aminoquinolines for the treatment and relapse prevention of vivax malaria.

【 授权许可】

Unknown   
© Starzengruber et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.