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.


OBJECTIVE
Diseases caused by multidrug-resistant bacteria are taking an important toll with respect to human morbidity and mortality. The most relevant antibiotic resistance genes come to human pathogens carried by plasmids, mainly using conjugation as a transmission mechanism. Here, we identified and characterized a series of compounds that were active against several plasmid groups of clinical relevance, in a wide variety of bacterial hosts. These inhibitors might be used for fighting antibiotic-resistance dissemination by inhibiting conjugation. Potential inhibitors could be used in specific settings (e.g., farm, fish factory, or even clinical settings) to investigate their effect in the eradication of undesired resistances.
Instituto de Biomedicina y Biotecnología de Cantabria, Universidad de Cantabria-Consejo Superior de Investigaciones Científicas, Santander, Cantabria, Spain.
María
M
Getino
Faculty of Science and Technology, Interamerican University of Puerto Rico, Metropolitan Campus, San Juan, Puerto Rico.
David J
DJ
Sanabria-Ríos
Instituto de Biomedicina y Biotecnología de Cantabria, Universidad de Cantabria-Consejo Superior de Investigaciones Científicas, Santander, Cantabria, Spain.
Raúl
R
Fernández-López
Instituto de Biomedicina y Biotecnología de Cantabria, Universidad de Cantabria-Consejo Superior de Investigaciones Científicas, Santander, Cantabria, Spain.
Javier
J
Campos-Gómez
Biomar Microbial Technologies, Parque Tecnológico de León, Armunia, León, Spain.
José M
JM
Sánchez-López
Biomar Microbial Technologies, Parque Tecnológico de León, Armunia, León, Spain.
Antonio
A
Fernández
Department of Chemistry, University of Puerto Rico, Rio Piedras Campus, San Juan, Puerto Rico.
Néstor M
NM
Carballeira
Instituto de Biomedicina y Biotecnología de Cantabria, Universidad de Cantabria-Consejo Superior de Investigaciones Científicas, Santander, Cantabria, Spain delacruz@unican.es.
Fernando
F
de la Cruz
D003227:Conjugation, Genetic / Q000187:drug effects*; D005227:Fatty Acids / Q000138:chemical synthesis / Q000378:metabolism*; D022761:Gene Transfer, Horizontal / Q000187:drug effects*; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000235:genetics; D010957:Plasmids / Q000378:metabolism*
D005227:Fatty Acids