Quimica

Differential Trypanocidal Activity of Novel Macrolide Antibiotics; Correlation to Genetic Lineage
Carolina Aquilino1., Maria Luisa Gonzalez Rubio1., Elena Maria Seco2, Leticia Escudero2, Laura Corvo1, Manuel Soto1, Manuel Fresno1, Francisco Malpartida2, Pedro Bonay1*
´ ´ ´ 1 Centro de Biologıa Molecular ‘‘Severo Ochoa’’, Universidad Autonoma de Madrid, Campus de Cantoblanco, Madrid, Spain, 2Centro Nacional de Biotecnologıa, Campus de Cantoblanco, Madrid, Spain

Abstract
Here we report the systematic study of the anti-trypanocidal activity of some new products derived from S. diastatus on 14 different T. cruzi strains spanning the six genetic lineages of T. cruzi. As the traditional growth inhibition curves giving similar IC50 showed great differences on antibiotic and lineagetested, we decided to preserve the wealth of information derived from each inhibition curve and used an algorithm related to potency of the drugs, combined in a matrix data set used to generate a cluster tree. The cluster thus generated based just on drug susceptibility data closely resembles the phylogenies of the lineages derived from genetic data and provides a novel approach to correlate geneticdata with phenotypes related to pathogenesis of Chagas disease. Furthermore we provide clues on the drugs mechanism of action.
Citation: Aquilino C, Gonzalez Rubio ML, Seco EM, Escudero L, Corvo L, et al. (2012) Differential Trypanocidal Activity of Novel Macrolide Antibiotics; Correlation to Genetic Lineage. PLoS ONE 7(7): e40901. doi:10.1371/journal.pone.0040901 ˜ Editor: Mauricio MartinsRodrigues, Federal University of Sao Paulo, Brazil Received January 20, 2012; Accepted June 14, 2012; Published July 31, 2012 Copyright: ß 2012 Aquilino et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding:This work was supported by Fondo de Investigaciones Sanitarias-Ministerio de Sanidad (FIS-PI08/0960) to PB and (FIS-PI08/0101) to MS; ChagasEpiNet (European VII framework Program) to MF; and Network RICET (Red Investigacion Cooperativa en Enfermedades Tropicales) from the FIS (Fondo de Investigaciones Sanitarias), Ministerio de Sanidad. Institutional support from Fundacion Ramon Areces. The fundershad no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: pbonay@cbm.uam.es . These authors contributed equally to the generation of results in this work.

Introduction
Chagas disease or American Trypanosomiasis is a chronic illness caused by theKinetoplastid protozoan Trypanosoma cruzi. At present it represents the third largest parasitic disease burden in the world and the largest in the western hemisphere. It is endemic in Central and South America with over 10 million people currently affected, with 40–100 million (15–20%of the whole Latin American population) at risk of acquiring the disease, killing around 15000 people annually [1,2].In the past decades, mainly because of increased population movements, the number of diagnosed cases has increased also in non-endemic countries in the Region of the Americas (Canada and United States of America), and in Europe (principally in Spain, Belgium, France, Italy, Switzerland and United Kingdom of Great Britain and Northern Ireland) [3–5] and the Western Pacific regions (Australia andJapan). This increase presents additional risks of transmission of the parasite through blood transfusion, congenital infection and organ transplantation [6]. The complex pathogenesis of the disease starts with a low mortality initial acute phase with generally mild and unspecific symptoms in which Th1 lymphocytes, IFN-gamma and macrophages are in charge of controlling parasite replication...