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Involvement of hpap2 and dgkA Genes in Colistin Resistance Mediated by mcr Determinants

Investigation published in Antibiotics

August 22nd, 2020

Plasmid-mediated colistin resistance (mcr) determinants are challenging the efficacy of polymyxins against Gram-negative pathogens. Among 10 mcr genes described so far, the major determinants mcr-1 and mcr-3 are found closely linked to hpap2 or dgkA genes, encoding a hypothetical phosphatidic acid phosphatase of type 2 (PAP2) and a diacylglycerol kinase, respectively, whose functions are still unknown. In this study, mcr-1, mcr-1–hpap2, mcr-3, and mcr-3–dgkA were expressed in Escherichia coli, and recombinant strains were analyzed to detect antimicrobial susceptibility and changes in the expression of genes involved in phospholipid metabolism. The mcr-1 or mcr-3 single genes were enough to drive growth on colistin selective media, although co-expression of linked genes conferred maximal antibiotic resistance. Expression of mcr determinants downregulated endogenous genes involved in lipopolysaccharide (LPS) modification or phospholipid recycling, although to different extents of repression: strong for arnB, ybjG, and pmrR; medium for eptA, lpxT, and dgkA; small for bacA and pgpB. Four of these genes (bacA, lpxT, pgpB, and ybjG) encode undecaprenyl pyrophosphate (UPP) phosphatases. In these conditions, cells presented resistance against bacitracin, an antibiotic that sequesters UPP from PAP2 enzymes. The hpap2 and dgkA genes might play a role in colistin resistance by compensating for phospholipid metabolism functions altered during LPS modification by colistin resistance determinants




Gallardo A., Ugarte-Ruiz M., Hernandez M., Miguela-Villoldo P., Rodriguez-Lazaro D., Dominguez L. and Quesada A.




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Involvement of hpap2 and dgkA Genes in Colistin Resistance Mediated by mcr Determinants

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Involvement of hpap2 and dgkA Genes in Colistin Resistance Mediated by mcr Determinants


Participants:

Universidad de ExtremaduraDepartamento de Bioquímica, Biología Molecular y Genética. Facultad de Veterinaria. Universidad de Extremadura (UNEX).

Universidad ComplutenseServicio de Zoonosis de Transmisión Alimentaria y Resistencia a Antimicrobianos (ZTA). Centro de Vigilancia Sanitaria Veterinaria (VISAVET). Universidad Complutense (UCM).

Instituto Tecnológico Agrario de Castilla y LeónLaboratorio de Biología Molecular y Microbiología. Instituto Tecnológico Agrario de Castilla y León (ITACyL).

Universidad de BurgosUnidad de Microbiología. Departamento de Biotecnología y Ciencia de los Alimentos. Universidad de Burgos (UBU).

Universidad de ExtremaduraInstituto Universitario de Biotecnología Ganadera y Cinegética (INBIO G+C). Universidad de Extremadura (UNEX).







Antibiotics
FACTOR YEAR Q
3.893 2019

PMID: 32842668

ISSN: 2079-6382



TITLE: Involvement of hpap2 and dgkA Genes in Colistin Resistance Mediated by mcr Determinants


JOURNAL: Antibiotics-Basel


NUMERACIÓN: 9(9):E531


AÑO: 2020


PUBLISHER: MDPI


AUTHORS: Gallardo A., Ugarte-Ruiz M., Hernandez M., Miguela-Villoldo P., Rodriguez-Lazaro D., Dominguez L. and Quesada A.


VISAVET PARTICIPANTS


2nd
María Ugarte Ruiz
4th
Pedro Miguela Villoldo
6th
Lucas Domínguez Rodríguez

DOI: https://doi.org/ 10.3390/antibiotics9090531


CITE THIS PUBLICATION:

Gallardo A., Ugarte-Ruiz M., Hernandez M., Miguela-Villoldo P., Rodriguez-Lazaro D., Dominguez L. and Quesada A. Involvement of hpap2 and dgkA Genes in Colistin Resistance Mediated by mcr Determinants. Antibiotics. 9(9):E531. 2020. (A). ISSN: 2079-6382. DOI: 10.3390/antibiotics9090531


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