TY - JOUR
T1 - Evolution of Enterococcus faecium in Response to a Combination of Daptomycin and Fosfomycin Reveals Distinct and Diverse Adaptive Strategies
AU - Supandy, Adeline
AU - Mehta, Heer H.
AU - Tran, Truc T.
AU - Miller, William R.
AU - Zhang, Rutan
AU - Xu, Libin
AU - Arias, Cesar A.
AU - Shamoo, Yousif
N1 - Funding Information:
Copyright © 2022 American Society for Microbiology. All Rights Reserved. Address correspondence to Yousif Shamoo, shamoo@rice.edu. The authors declare a conflict of interest. This work was supported by National Institutes of Health, National Institute of Allergy and Infectious Diseases grants R01A1080714 to Y.S., K08 AI135093-01A1 to W.R.M., R01AI136979 to L.X., R01-AI148342, R01-AI134637, P01-AI152999, and K24-AI121296 to C.A.A. Funding agencies did not play a role in experimental design, performance or analysis. C.A.A. has received grants from Merck, MeMed Diagnostics, and Entasis Therapeutics. W.R.M. has received a grant from Merck, and honoraria from Achaogen and Shionogi. T.T.T. has received a grant from Merck. Received 20 December 2021 Returned for modification 31 January 2022 Accepted 7 April 2022 Published 11 May 2022
Funding Information:
This work was supported by National Institutes of Health, National Institute of Allergy and Infectious Diseases, grants R01A1080714 to Y.S., K08 AI135093-01A1 to W.R.M., R01AI136979 to L.X., and R01-AI148342, R01-AI134637, P01-AI152999, and K24-AI121296 to C.A.A. Funding agencies did not play a role in experimental design, performance, or analysis. C.A.A. has received grants from Merck, MeMed Diagnostics, and Entasis Therapeutics. W.R.M. has received a grant from Merck and honoraria from Achaogen and Shionogi. T.T.T. has received a grant from Merck.
Publisher Copyright:
© 2022 American Society for Microbiology.
PY - 2022/6
Y1 - 2022/6
N2 - Infections caused by vancomycin-resistant Enterococcus faecium (VREfm) are an important public health threat. VREfm isolates have become increasingly resistant to the front-line antibiotic daptomycin (DAP). As such, the use of DAP combination therapies with other antibiotics like fosfomycin (FOS) has received increased attention. Antibiotic combinations could extend the efficacy of currently available antibiotics and potentially delay the onset of further resistance. We investigated the potential for E. faecium HOU503, a clinical VREfm isolate that is DAP and FOS susceptible, to develop resistance to a DAP-FOS combination. Of particular interest was whether the genetic drivers for DAP-FOS resistance might be epistatic and, thus, potentially decrease the efficacy of a combinatorial approach in either inhibiting VREfm or in delaying the onset of resistance. We show that resistance to DAP-FOS could be achieved by independent mutations to proteins responsible for cell wall synthesis for FOS and in altering membrane dynamics for DAP. However, we did not observe genetic drivers that exhibited substantial cross-drug epistasis that could undermine the DAP-FOS combination. Of interest was that FOS resistance in HOU503 was largely mediated by changes in phosphoenolpyruvate (PEP) flux as a result of mutations in pyruvate kinase (pyk). Increasing PEP flux could be a readily accessible mechanism for FOS resistance in many pathogens. Importantly, we show that HOU503 was able to develop DAP resistance through a variety of biochemical mechanisms and was able to employ different adaptive strategies. Finally, we showed that the addition of FOS can prolong the efficacy of DAP and slow down DAP resistance in vitro.
AB - Infections caused by vancomycin-resistant Enterococcus faecium (VREfm) are an important public health threat. VREfm isolates have become increasingly resistant to the front-line antibiotic daptomycin (DAP). As such, the use of DAP combination therapies with other antibiotics like fosfomycin (FOS) has received increased attention. Antibiotic combinations could extend the efficacy of currently available antibiotics and potentially delay the onset of further resistance. We investigated the potential for E. faecium HOU503, a clinical VREfm isolate that is DAP and FOS susceptible, to develop resistance to a DAP-FOS combination. Of particular interest was whether the genetic drivers for DAP-FOS resistance might be epistatic and, thus, potentially decrease the efficacy of a combinatorial approach in either inhibiting VREfm or in delaying the onset of resistance. We show that resistance to DAP-FOS could be achieved by independent mutations to proteins responsible for cell wall synthesis for FOS and in altering membrane dynamics for DAP. However, we did not observe genetic drivers that exhibited substantial cross-drug epistasis that could undermine the DAP-FOS combination. Of interest was that FOS resistance in HOU503 was largely mediated by changes in phosphoenolpyruvate (PEP) flux as a result of mutations in pyruvate kinase (pyk). Increasing PEP flux could be a readily accessible mechanism for FOS resistance in many pathogens. Importantly, we show that HOU503 was able to develop DAP resistance through a variety of biochemical mechanisms and was able to employ different adaptive strategies. Finally, we showed that the addition of FOS can prolong the efficacy of DAP and slow down DAP resistance in vitro.
KW - Enterococcus
KW - antibiotic resistance
KW - daptomycin
KW - drug resistance evolution
KW - fosfomycin
KW - Vancomycin-Resistant Enterococci/genetics
KW - Anti-Bacterial Agents/pharmacology
KW - Microbial Sensitivity Tests
KW - Daptomycin/pharmacology
KW - Fosfomycin/pharmacology
KW - Drug Resistance, Bacterial/genetics
KW - Enterococcus faecium/genetics
KW - Evolution, Molecular
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UR - http://www.scopus.com/inward/citedby.url?scp=85132454023&partnerID=8YFLogxK
U2 - 10.1128/aac.02333-21
DO - 10.1128/aac.02333-21
M3 - Article
C2 - 35543524
AN - SCOPUS:85132454023
SN - 0066-4804
VL - 66
SP - e0233321
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
IS - 6
ER -