Synthetic Fatty Acids Prevent Plasmid-Mediated Horizontal Gene Transfer

Bacterial conjugation constitutes a major horizontal gene transfer mechanism for the dissemination of antibiotic resistance genes among human pathogens. Antibiotic resistance spread could be halted or diminished by molecules that interfere with the conjugation process. In this work, synthetic 2-alkynoic fatty acids were identified as a novel class of conjugation inhibitors. Their chemical properties were investigated by using the prototype 2-hexadecynoic acid and its derivatives. Essential features of effective inhibitors were the carboxylic group, an optimal long aliphatic chain of 16 carbon atoms, and one unsaturation. Chemical modification of these groups led to inactive or less-active derivatives. Conjugation inhibitors were found to act on the donor cell, affecting a wide number of pathogenic bacterial hosts, including Escherichia, Salmonella, Pseudomonas, and Acinetobacter spp. Conjugation inhibitors were active in inhibiting transfer of IncF, IncW, and IncH plasmids, moderately active against IncI, IncL/M, and IncX plasmids, and inactive against IncP and IncN plasmids. Importantly, the use of 2-hexadecynoic acid avoided the spread of a derepressed IncF plasmid into a recipient population, demonstrating the feasibility of abolishing the dissemination of antimicrobial resistances by blocking bacterial conjugation.The work performed by the F.D.L.C. group was supported by grants BFU2011-26608 from the Spanish Ministry of Economy and Competitiveness and 612146/FP7-ICT-2013-10 and 282004/FP7-HEALTH-2011-2.3.1-2 from the European Seventh Framework Programme. The work performed by M.G. was supported by a Ph.D. fellowship from the University of Cantabria. The work performed by D.J.S.-R. was supported by the National Center for Research Resources and the National Institute of General Medical Sciences of the National Institutes of Health through grant no. 5P20GM103475-13 and the Interamerican University of Puerto Rico. The work performed by J.C.-G. was supported by an EMBO postdoctoral fellowship, ASTF 402-2010. The work performed by Biomar Microbial Technologies was supported by grant 282004/FP7-HEALTH-2011-2.3.1-2 from the European Seventh Framework Programme.USD 2,190 APC fee funded by the EC FP7 Post-Grant Open Access PilotPeer reviewe