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Emergence of Meropenem Resistance Among Cefotaxime Non-susceptible Streptococcus pneumoniae: Evidence and Challenges

The principal causative agent of acute bacterial meningitis (ABM) in children and the elderly is Streptococcus pneumoniae, with a widespread increase in penicillin resistance. Resistance is due to non-synonymous single-nucleotide polymorphisms (nsSNPs) that alter the penicillin-binding proteins (PBP...

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Autores principales: Varghese, Rosemol, Basu, Soumya, Neeravi, Ayyanraj, Pragasam, Agilakumari, Aravind, V., Gupta, Richa, Miraclin, Angel, Ramaiah, Sudha, Anbarasu, Anand, Veeraraghavan, Balaji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8853538/
https://www.ncbi.nlm.nih.gov/pubmed/35185834
http://dx.doi.org/10.3389/fmicb.2021.810414
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author Varghese, Rosemol
Basu, Soumya
Neeravi, Ayyanraj
Pragasam, Agilakumari
Aravind, V.
Gupta, Richa
Miraclin, Angel
Ramaiah, Sudha
Anbarasu, Anand
Veeraraghavan, Balaji
author_facet Varghese, Rosemol
Basu, Soumya
Neeravi, Ayyanraj
Pragasam, Agilakumari
Aravind, V.
Gupta, Richa
Miraclin, Angel
Ramaiah, Sudha
Anbarasu, Anand
Veeraraghavan, Balaji
author_sort Varghese, Rosemol
collection PubMed
description The principal causative agent of acute bacterial meningitis (ABM) in children and the elderly is Streptococcus pneumoniae, with a widespread increase in penicillin resistance. Resistance is due to non-synonymous single-nucleotide polymorphisms (nsSNPs) that alter the penicillin-binding proteins (PBPs), the targets for all β-lactam drugs. Hence, resistance against one β-lactam antibiotic may positively select another. Since meropenem is an alternative to cefotaxime in meningeal infections, we aim to identify whether nsSNPs in the PBPs causing penicillin and cefotaxime resistance can decrease the pneumococcal susceptibility to meropenem. Comparison of the nsSNPs in the PBPs between the cefotaxime-resistant Indian (n = 33) and global isolates (n = 28) revealed that nsSNPs in PBP1A alone elevated meropenem minimal inhibitory concentrations (MICs) to 0.12 μg/ml, and nsSNPs in both PBP2X and 2B combined with PBP1A increases MIC to ≥ 0.25 μg/ml. Molecular docking confirmed the decrease in the PBP drug binding affinity due to the nsSNPs, thereby increasing the inhibition potential and the MIC values, leading to resistance. Structural dynamics and thermodynamic stability pattern in PBPs as a result of mutations further depicted that the accumulation of certain nsSNPs in the functional domains reduced the drug affinity without majorly affecting the overall stability of the proteins. Restricting meropenem usage and promoting combination therapy with antibiotics having non-PBPs as targets to treat cefotaxime non-susceptible S. pneumoniae meningitis can prevent the selection of β-lactam resistance.
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spelling pubmed-88535382022-02-18 Emergence of Meropenem Resistance Among Cefotaxime Non-susceptible Streptococcus pneumoniae: Evidence and Challenges Varghese, Rosemol Basu, Soumya Neeravi, Ayyanraj Pragasam, Agilakumari Aravind, V. Gupta, Richa Miraclin, Angel Ramaiah, Sudha Anbarasu, Anand Veeraraghavan, Balaji Front Microbiol Microbiology The principal causative agent of acute bacterial meningitis (ABM) in children and the elderly is Streptococcus pneumoniae, with a widespread increase in penicillin resistance. Resistance is due to non-synonymous single-nucleotide polymorphisms (nsSNPs) that alter the penicillin-binding proteins (PBPs), the targets for all β-lactam drugs. Hence, resistance against one β-lactam antibiotic may positively select another. Since meropenem is an alternative to cefotaxime in meningeal infections, we aim to identify whether nsSNPs in the PBPs causing penicillin and cefotaxime resistance can decrease the pneumococcal susceptibility to meropenem. Comparison of the nsSNPs in the PBPs between the cefotaxime-resistant Indian (n = 33) and global isolates (n = 28) revealed that nsSNPs in PBP1A alone elevated meropenem minimal inhibitory concentrations (MICs) to 0.12 μg/ml, and nsSNPs in both PBP2X and 2B combined with PBP1A increases MIC to ≥ 0.25 μg/ml. Molecular docking confirmed the decrease in the PBP drug binding affinity due to the nsSNPs, thereby increasing the inhibition potential and the MIC values, leading to resistance. Structural dynamics and thermodynamic stability pattern in PBPs as a result of mutations further depicted that the accumulation of certain nsSNPs in the functional domains reduced the drug affinity without majorly affecting the overall stability of the proteins. Restricting meropenem usage and promoting combination therapy with antibiotics having non-PBPs as targets to treat cefotaxime non-susceptible S. pneumoniae meningitis can prevent the selection of β-lactam resistance. Frontiers Media S.A. 2022-02-03 /pmc/articles/PMC8853538/ /pubmed/35185834 http://dx.doi.org/10.3389/fmicb.2021.810414 Text en Copyright © 2022 Varghese, Basu, Neeravi, Pragasam, Aravind, Gupta, Miraclin, Ramaiah, Anbarasu and Veeraraghavan. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Microbiology
Varghese, Rosemol
Basu, Soumya
Neeravi, Ayyanraj
Pragasam, Agilakumari
Aravind, V.
Gupta, Richa
Miraclin, Angel
Ramaiah, Sudha
Anbarasu, Anand
Veeraraghavan, Balaji
Emergence of Meropenem Resistance Among Cefotaxime Non-susceptible Streptococcus pneumoniae: Evidence and Challenges
title Emergence of Meropenem Resistance Among Cefotaxime Non-susceptible Streptococcus pneumoniae: Evidence and Challenges
title_full Emergence of Meropenem Resistance Among Cefotaxime Non-susceptible Streptococcus pneumoniae: Evidence and Challenges
title_fullStr Emergence of Meropenem Resistance Among Cefotaxime Non-susceptible Streptococcus pneumoniae: Evidence and Challenges
title_full_unstemmed Emergence of Meropenem Resistance Among Cefotaxime Non-susceptible Streptococcus pneumoniae: Evidence and Challenges
title_short Emergence of Meropenem Resistance Among Cefotaxime Non-susceptible Streptococcus pneumoniae: Evidence and Challenges
title_sort emergence of meropenem resistance among cefotaxime non-susceptible streptococcus pneumoniae: evidence and challenges
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8853538/
https://www.ncbi.nlm.nih.gov/pubmed/35185834
http://dx.doi.org/10.3389/fmicb.2021.810414
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