Universidad del Desarrollo

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Daptomycin-Resistant Enterococcus faecalis Diverts the Antibiotic Molecule from the Division Septum and Remodels Cell Membrane Phospholipids
(2013)
Truc T. Tran
;
Diana Panesso
;
Nagendra N. Mishra
;
Eugenia Mileykovskaya
;
Ziqianq Guan
<jats:title>ABSTRACT</jats:title> <jats:p> Treatment of multidrug-resistant enterococci has become a challenging clinical problem in hospitals around the world due to the lack of reliable therapeutic options. Daptomycin (DAP), a cell membrane-targeting cationic antimicrobial lipopeptide, is the only antibiotic with <jats:italic>in vitro</jats:italic> bactericidal activity against vancomycin-resistant enterococci (VRE). However, the clinical use of DAP against VRE is threatened by emergence of resistance during therapy, but the mechanisms leading to DAP resistance are not fully understood. The mechanism of action of DAP involves interactions with the cell membrane in a calcium-dependent manner, mainly at the level of the bacterial septum. Previously, we demonstrated that development of DAP resistance in vancomycin-resistant <jats:named-content content-type="genus-species">Enterococcus faecalis</jats:named-content> is associated with mutations in genes encoding proteins with two main functions, (i) control of the cell envelope stress response to antibiotics and antimicrobial peptides (LiaFSR system) and (ii) cell membrane phospholipid metabolism (glycerophosphoryl diester phosphodiesterase and cardiolipin synthase). In this work, we show that these VRE can resist DAP-elicited cell membrane damage by diverting the antibiotic away from its principal target (division septum) to other distinct cell membrane regions. DAP septal diversion by DAP-resistant <jats:named-content content-type="genus-species">E. faecalis</jats:named-content> is mediated by initial redistribution of cell membrane cardiolipin-rich microdomains associated with a single amino acid deletion within the transmembrane protein LiaF (a member of a three-component regulatory system [LiaFSR] involved in cell envelope homeostasis). Full expression of DAP resistance requires additional mutations in enzymes (glycerophosphoryl diester phosphodiesterase and cardiolipin synthase) that alter cell membrane phospholipid content. Our findings describe a novel mechanism of bacterial resistance to cationic antimicrobial peptides. </jats:p> <jats:p> <jats:bold>IMPORTANCE</jats:bold> The emergence of antibiotic resistance in bacterial pathogens is a threat to public health. Understanding the mechanisms of resistance is of crucial importance to develop new strategies to combat multidrug-resistant microorganisms. Vancomycin-resistant enterococci (VRE) are one of the most recalcitrant hospital-associated pathogens against which new therapies are urgently needed. Daptomycin (DAP) is a calcium-decorated antimicrobial lipopeptide whose target is the bacterial cell membrane. A current paradigm suggests that Gram-positive bacteria become resistant to cationic antimicrobial peptides via an electrostatic repulsion of the antibiotic molecule from a more positively charged cell surface. In this work, we provide evidence that VRE use a novel strategy to avoid DAP-elicited killing. Instead of “repelling” the antibiotic from the cell surface, VRE diverts the antibiotic molecule from the septum and “traps” it in distinct membrane regions. We provide genetic and biochemical bases responsible for the mechanism of resistance and disclose new targets for potential antimicrobial development. </jats:p>
5Scopus© Citations 142
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Multisite Detection of Tn
<i>1549</i>
-Mediated
<i>vanB</i>
Vancomycin Resistance in Multidrug-Resistant Enterococcus faecalis ST6 in Texas and Florida
(2023)
Shelby R. Simar
;
Truc T. Tran
;
Kirsten B. Rydell
;
Diana Panesso
;
German A. Contreras
<jats:p> In the United States, <jats:italic>vanB</jats:italic> -mediated resistance in enterococci is rare. We characterized three sequence type (ST) 6, vancomycin-resistant <jats:named-content content-type="genus-species">Enterococcus faecalis</jats:named-content> isolates causing bacteremia in unique patients in spatiotemporally distinct settings. </jats:p>
7 1Scopus© Citations 3
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Genomic Epidemiology of Vancomycin-Resistant Enterococcus faecium (VREfm) in Latin America: Revisiting The Global VRE Population Structure
(2020)
Rafael Rios
;
Jinnethe Reyes
;
Lina P. Carvajal
;
Sandra Rincon
;
Diana Panesso
<jats:title>Abstract</jats:title><jats:p>Little is known about the population structure of vancomycin-resistant <jats:italic>Enterococcus faecium</jats:italic> (VR<jats:italic>Efm</jats:italic>) in Latin America (LATAM). Here, we provide a complete genomic characterization of 55 representative Latin American VR<jats:italic>Efm</jats:italic> recovered from 1998–2015 in 5 countries. The LATAM VR<jats:italic>Efm</jats:italic> population is structured into two main clinical clades without geographical clustering. Using the LATAM genomes, we reconstructed the global population of VR<jats:italic>Efm</jats:italic> by including 285 genomes from 36 countries spanning from 1946 to 2017. In contrast to previous studies, our results show an early branching of animal related isolates and a further split of clinical isolates into two sub-clades within clade A. The overall phylogenomic structure of clade A was highly dependent on recombination (54% of the genome) and the split between clades A and B was estimated to have occurred more than 2,765 years ago. Furthermore, our molecular clock calculations suggest the branching of animal isolates and clinical clades occurred ~502 years ago whereas the split within the clinical clade occurred ~302 years ago (previous studies showed a more recent split between clinical an animal branches around ~74 years ago). By including isolates from Latin America, we present novel insights into the population structure of VR<jats:italic>Efm</jats:italic> and revisit the evolution of these pathogens.</jats:p>
1Scopus© Citations 47 1
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Resistencia a antibióticos de última línea en cocos Gram positivos: la era posterior a la vancomicina
(2014)
Sandra Rincón
;
Diana Panesso
;
Lorena Díaz
;
Lina P. Carvajal
;
Jinnethe Reyes
Scopus© Citations 30 1

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