Emergence of a daptomycin-non-susceptible Enterococcus faecium strain that encodes mutations in DNA repair genes after high-dose daptomycin therapy

Matono, Takashi; Hayakawa, Kayoko; Hirai, Risen; Tanimura, Akira; Yamamoto, Kei; Fujiya, Yoshihiro; Mawatari, Momoko; Kutsuna, Satoshi; Takeshita, Nozomi; Mezaki, Kazuhisa; Ohmagari, Norio; Miyoshi‐Akiyama, Tohru

doi:10.1186/s13104-016-2003-9

Cited by 14 publications

(10 citation statements)

References 20 publications

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“…Daptomycin was approved by the FDA in 2003 and marketed in the United States under the trade name Cubicin by Cubist Pharmaceuticals Inc. (now Merck & Co.) for the treatment of skin and skin structure infections and right-side endocarditis caused by MRSA, as well as patients with prolonged MRSA bacteremia (>7 days) which are at high risk for metastatic complications and death. As daptomycin has been introduced to the market for over 15 years, there are increasing reported cases of infection caused by daptomycin-resistant Gram-positive clinical pathogens such as S. aureus , Enterococci , and Streptococci in clinical settings in recent years. − As the first-in-class lipodepsipeptide antibiotic with a distinct mechanism of action, daptomycin has the potential to be derivatized to produce next-generation daptomycin-based antibiotics as seen in the successful development of several generations of β-lactam-based antibiotics.…”

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confidence: 99%

Establishing the Structure–Activity Relationship of Daptomycin

Chow

Jin

et al. 2020

ACS Med. Chem. Lett.

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Daptomycin is effective in treating infections caused by antibiotic-resistant Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE), and vancomycin-resistant S. aureus (VRSA). Due to its distinct mechanism of action toward multidrug-resistant bacteria, daptomycin provides an attractive structural motif to generate new daptomycin-based antibiotics to combat the problem of bacterial resistance. In this study, we used the total synthesis method to produce daptomycin analogues with a variety in terms of types and sites of modifications. Five classes of daptomycin analogues were synthesized, and the antimicrobial activities of the analogues were analyzed by several biological assays. From this study, we established a comprehensive structure–activity relationship of daptomycin which will lay the foundation for the further development of daptomycin-based antibiotics.

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confidence: 99%

Establishing the Structure–Activity Relationship of Daptomycin

Chow

Jin

et al. 2020

ACS Med. Chem. Lett.

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“…To evaluate the effects of these identified mutations, we performed rifampin mutagenicity assays and confirmed that the 2011 ST55 and 2016 ST4 isolates displayed a hypermutator phenotype. Previous work has evaluated the effects of mutated mutS and mutL genes in emerging antimicrobial resistance in Enterococcus faecium with mixed conclusions (33,34). While one study did not identify a hypermutator phenotype in two E. faecium strains with mutL and mutS mutations that developed linezolid resistance during therapy, another case presentation described recJ and mutL mutations in a daptomycin-nonsusceptible E. faecium blood culture isolate from an endocarditis patient (33,34).…”

Section: Discussionmentioning

confidence: 99%

Long-Term Colonization Dynamics of Enterococcus faecalis in Implanted Devices in Research Macaques

Lieberman

Tyne

Dzink-Fox

et al. 2018

Appl Environ Microbiol

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is a common opportunistic pathogen that colonizes cephalic recording chambers (CRCs) of macaques used in cognitive neuroscience research. We previously characterized 15 strains isolated from macaques at the Massachusetts Institute of Technology (MIT) in 2011. The goal of this study was to examine how a 2014 protocol change prohibiting the use of antimicrobials within CRCs affected colonizing strains. We collected 20 isolates from 10 macaques between 2013 and 2017 for comparison to 4 isolates previously characterized in 2011 with respect to the sequence type (ST) distribution, antimicrobial resistance, biofilm formation, and changes in genes that might confer a survival advantage. ST4 and ST55 were predominant among the isolates characterized in 2011, whereas the less antimicrobial-resistant lineage ST48 emerged to dominance after 2013. Two macaques remained colonized by ST4 and ST55 strains for 5 and 4 years, respectively. While the antimicrobial resistance and virulence factors identified in these ST4 and ST55 strains remained relatively stable, we detected an increase in biofilm formation ability over time in both isolates. We also found that ST48 strains were typically robust biofilm formers, which could explain why this ST increased in prevalence. Finally, we identified mutations in the DNA mismatch repair genes and in separate ST55 and ST4 strains and confirmed that strains bearing these mutations displayed a hypermutator phenotype. The presence of a hypermutator phenotype may complicate future antimicrobial treatment for clinically relevant infections in macaques. is a common cause of health care-associated infections in humans, largely due to its ability to persist in the hospital environment, colonize patients, acquire antimicrobial resistance, and form biofilms. Understanding how enterococci evolve in health care settings provides insight into factors affecting enterococcal survival and persistence. Macaques used in neuroscience research have long-term cranial implants that, despite best practices, often become colonized by This provides a unique opportunity to noninvasively examine the evolution of enterococci on a long-term indwelling device. We collected strains from cephalic implants over a 7-year period and characterized the sequence type, antimicrobial resistance, virulence factors, biofilm production, and hypermutator phenotypes. Improved antimicrobial stewardship allowed a less-antimicrobial-resistant strain to predominate at the implant interface, potentially improving antimicrobial treatment outcomes if future clinical infections occur. Biofilm formation appears to play an important role in the persistence of the strains associated with these implants.

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“…Mutations of DNA “mismatch repair” genes in a DAP-R pleiotropic phenotype were discovered in a clinical isolate of Ent. faecium [ 369 ].…”

Section: Resistance Problems Related To Gram-positive Pathogensmentioning

confidence: 99%

Multidrug Resistance (MDR) and Collateral Sensitivity in Bacteria, with Special Attention to Genetic and Evolutionary Aspects and to the Perspectives of Antimicrobial Peptides—A Review

Fodor

Abate²,

Deák

et al. 2020

Pathogens

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Antibiotic poly-resistance (multidrug-, extreme-, and pan-drug resistance) is controlled by adaptive evolution. Darwinian and Lamarckian interpretations of resistance evolution are discussed. Arguments for, and against, pessimistic forecasts on a fatal “post-antibiotic era” are evaluated. In commensal niches, the appearance of a new antibiotic resistance often reduces fitness, but compensatory mutations may counteract this tendency. The appearance of new antibiotic resistance is frequently accompanied by a collateral sensitivity to other resistances. Organisms with an expanding open pan-genome, such as Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae, can withstand an increased number of resistances by exploiting their evolutionary plasticity and disseminating clonally or poly-clonally. Multidrug-resistant pathogen clones can become predominant under antibiotic stress conditions but, under the influence of negative frequency-dependent selection, are prevented from rising to dominance in a population in a commensal niche. Antimicrobial peptides have a great potential to combat multidrug resistance, since antibiotic-resistant bacteria have shown a high frequency of collateral sensitivity to antimicrobial peptides. In addition, the mobility patterns of antibiotic resistance, and antimicrobial peptide resistance, genes are completely different. The integron trade in commensal niches is fortunately limited by the species-specificity of resistance genes. Hence, we theorize that the suggested post-antibiotic era has not yet come, and indeed might never come.

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Emergence of a daptomycin-non-susceptible Enterococcus faecium strain that encodes mutations in DNA repair genes after high-dose daptomycin therapy

Cited by 14 publications

References 20 publications

Establishing the Structure–Activity Relationship of Daptomycin

Establishing the Structure–Activity Relationship of Daptomycin

Long-Term Colonization Dynamics of Enterococcus faecalis in Implanted Devices in Research Macaques

Multidrug Resistance (MDR) and Collateral Sensitivity in Bacteria, with Special Attention to Genetic and Evolutionary Aspects and to the Perspectives of Antimicrobial Peptides—A Review

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