Paradoxical Hypersusceptibility of Drug-resistant Mycobacterium tuberculosis to β-lactam Antibiotics

Keira A. Cohen, Tal El-Hay, Kelly L. Wyres, Omer Weissbrod, Vanisha Munsamy, Chen Yanover, Ranit Aharonov, Oded Shaham, Thomas C. Conway, Yaara Goldschmidt, William R. Bishai, Alexander S. Pym

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Mycobacterium tuberculosis (M. tuberculosis) is considered innately resistant to β-lactam antibiotics. However, there is evidence that susceptibility to β-lactam antibiotics in combination with β–lactamase inhibitors is variable among clinical isolates, and these may present therapeutic options for drug-resistant cases. Here we report our investigation of susceptibility to β-lactam/β–lactamase inhibitor combinations among clinical isolates of M. tuberculosis, and the use of comparative genomics to understand the observed heterogeneity in susceptibility. Eighty-nine South African clinical isolates of varying first and second-line drug susceptibility patterns and two reference strains of M. tuberculosis underwent minimum inhibitory concentration (MIC) determination to two β-lactams: amoxicillin and meropenem, both alone and in combination with clavulanate, a β–lactamase inhibitor. 41/91 (45%) of tested isolates were found to be hypersusceptible to amoxicillin/clavulanate relative to reference strains, including 14/24 (58%) of multiple drug-resistant (MDR) and 22/38 (58%) of extensively drug-resistant (XDR) isolates. Genome-wide polymorphisms identified using whole-genome sequencing were used in a phylogenetically-aware linear mixed model to identify polymorphisms associated with amoxicillin/clavulanate susceptibility. Susceptibility to amoxicillin/clavulanate was over-represented among isolates within a specific clade (LAM4), in particular among XDR strains. Twelve sets of polymorphisms were identified as putative markers of amoxicillin/clavulanate susceptibility, five of which were confined solely to LAM4. Within the LAM4 clade, ‘paradoxical hypersusceptibility’ to amoxicillin/clavulanate has evolved in parallel to first and second-line drug resistance. Given the high prevalence of LAM4 among XDR TB in South Africa, our data support an expanded role for β-lactam/β-lactamase inhibitor combinations for treatment of drug-resistant M. tuberculosis.

Original languageEnglish
Pages (from-to)170-179
Number of pages10
JournalEBioMedicine
Volume9
DOIs
Publication statusPublished - 1 Jan 2016
Externally publishedYes

Keywords

  • Antimicrobial chemotherapy
  • Beta-lactam antibiotics
  • Extensively drug resistant (XDR)
  • Multi-drug resistant (MDR)
  • pks12
  • Recombination
  • tuberculosis

Cite this

Cohen, Keira A. ; El-Hay, Tal ; Wyres, Kelly L. ; Weissbrod, Omer ; Munsamy, Vanisha ; Yanover, Chen ; Aharonov, Ranit ; Shaham, Oded ; Conway, Thomas C. ; Goldschmidt, Yaara ; Bishai, William R. ; Pym, Alexander S. / Paradoxical Hypersusceptibility of Drug-resistant Mycobacterium tuberculosis to β-lactam Antibiotics. In: EBioMedicine. 2016 ; Vol. 9. pp. 170-179.
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abstract = "Mycobacterium tuberculosis (M. tuberculosis) is considered innately resistant to β-lactam antibiotics. However, there is evidence that susceptibility to β-lactam antibiotics in combination with β–lactamase inhibitors is variable among clinical isolates, and these may present therapeutic options for drug-resistant cases. Here we report our investigation of susceptibility to β-lactam/β–lactamase inhibitor combinations among clinical isolates of M. tuberculosis, and the use of comparative genomics to understand the observed heterogeneity in susceptibility. Eighty-nine South African clinical isolates of varying first and second-line drug susceptibility patterns and two reference strains of M. tuberculosis underwent minimum inhibitory concentration (MIC) determination to two β-lactams: amoxicillin and meropenem, both alone and in combination with clavulanate, a β–lactamase inhibitor. 41/91 (45{\%}) of tested isolates were found to be hypersusceptible to amoxicillin/clavulanate relative to reference strains, including 14/24 (58{\%}) of multiple drug-resistant (MDR) and 22/38 (58{\%}) of extensively drug-resistant (XDR) isolates. Genome-wide polymorphisms identified using whole-genome sequencing were used in a phylogenetically-aware linear mixed model to identify polymorphisms associated with amoxicillin/clavulanate susceptibility. Susceptibility to amoxicillin/clavulanate was over-represented among isolates within a specific clade (LAM4), in particular among XDR strains. Twelve sets of polymorphisms were identified as putative markers of amoxicillin/clavulanate susceptibility, five of which were confined solely to LAM4. Within the LAM4 clade, ‘paradoxical hypersusceptibility’ to amoxicillin/clavulanate has evolved in parallel to first and second-line drug resistance. Given the high prevalence of LAM4 among XDR TB in South Africa, our data support an expanded role for β-lactam/β-lactamase inhibitor combinations for treatment of drug-resistant M. tuberculosis.",
keywords = "Antimicrobial chemotherapy, Beta-lactam antibiotics, Extensively drug resistant (XDR), Multi-drug resistant (MDR), pks12, Recombination, tuberculosis",
author = "Cohen, {Keira A.} and Tal El-Hay and Wyres, {Kelly L.} and Omer Weissbrod and Vanisha Munsamy and Chen Yanover and Ranit Aharonov and Oded Shaham and Conway, {Thomas C.} and Yaara Goldschmidt and Bishai, {William R.} and Pym, {Alexander S.}",
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Cohen, KA, El-Hay, T, Wyres, KL, Weissbrod, O, Munsamy, V, Yanover, C, Aharonov, R, Shaham, O, Conway, TC, Goldschmidt, Y, Bishai, WR & Pym, AS 2016, 'Paradoxical Hypersusceptibility of Drug-resistant Mycobacterium tuberculosis to β-lactam Antibiotics' EBioMedicine, vol. 9, pp. 170-179. https://doi.org/10.1016/j.ebiom.2016.05.041

Paradoxical Hypersusceptibility of Drug-resistant Mycobacterium tuberculosis to β-lactam Antibiotics. / Cohen, Keira A.; El-Hay, Tal; Wyres, Kelly L.; Weissbrod, Omer; Munsamy, Vanisha; Yanover, Chen; Aharonov, Ranit; Shaham, Oded; Conway, Thomas C.; Goldschmidt, Yaara; Bishai, William R.; Pym, Alexander S.

In: EBioMedicine, Vol. 9, 01.01.2016, p. 170-179.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Paradoxical Hypersusceptibility of Drug-resistant Mycobacterium tuberculosis to β-lactam Antibiotics

AU - Cohen, Keira A.

AU - El-Hay, Tal

AU - Wyres, Kelly L.

AU - Weissbrod, Omer

AU - Munsamy, Vanisha

AU - Yanover, Chen

AU - Aharonov, Ranit

AU - Shaham, Oded

AU - Conway, Thomas C.

AU - Goldschmidt, Yaara

AU - Bishai, William R.

AU - Pym, Alexander S.

PY - 2016/1/1

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N2 - Mycobacterium tuberculosis (M. tuberculosis) is considered innately resistant to β-lactam antibiotics. However, there is evidence that susceptibility to β-lactam antibiotics in combination with β–lactamase inhibitors is variable among clinical isolates, and these may present therapeutic options for drug-resistant cases. Here we report our investigation of susceptibility to β-lactam/β–lactamase inhibitor combinations among clinical isolates of M. tuberculosis, and the use of comparative genomics to understand the observed heterogeneity in susceptibility. Eighty-nine South African clinical isolates of varying first and second-line drug susceptibility patterns and two reference strains of M. tuberculosis underwent minimum inhibitory concentration (MIC) determination to two β-lactams: amoxicillin and meropenem, both alone and in combination with clavulanate, a β–lactamase inhibitor. 41/91 (45%) of tested isolates were found to be hypersusceptible to amoxicillin/clavulanate relative to reference strains, including 14/24 (58%) of multiple drug-resistant (MDR) and 22/38 (58%) of extensively drug-resistant (XDR) isolates. Genome-wide polymorphisms identified using whole-genome sequencing were used in a phylogenetically-aware linear mixed model to identify polymorphisms associated with amoxicillin/clavulanate susceptibility. Susceptibility to amoxicillin/clavulanate was over-represented among isolates within a specific clade (LAM4), in particular among XDR strains. Twelve sets of polymorphisms were identified as putative markers of amoxicillin/clavulanate susceptibility, five of which were confined solely to LAM4. Within the LAM4 clade, ‘paradoxical hypersusceptibility’ to amoxicillin/clavulanate has evolved in parallel to first and second-line drug resistance. Given the high prevalence of LAM4 among XDR TB in South Africa, our data support an expanded role for β-lactam/β-lactamase inhibitor combinations for treatment of drug-resistant M. tuberculosis.

AB - Mycobacterium tuberculosis (M. tuberculosis) is considered innately resistant to β-lactam antibiotics. However, there is evidence that susceptibility to β-lactam antibiotics in combination with β–lactamase inhibitors is variable among clinical isolates, and these may present therapeutic options for drug-resistant cases. Here we report our investigation of susceptibility to β-lactam/β–lactamase inhibitor combinations among clinical isolates of M. tuberculosis, and the use of comparative genomics to understand the observed heterogeneity in susceptibility. Eighty-nine South African clinical isolates of varying first and second-line drug susceptibility patterns and two reference strains of M. tuberculosis underwent minimum inhibitory concentration (MIC) determination to two β-lactams: amoxicillin and meropenem, both alone and in combination with clavulanate, a β–lactamase inhibitor. 41/91 (45%) of tested isolates were found to be hypersusceptible to amoxicillin/clavulanate relative to reference strains, including 14/24 (58%) of multiple drug-resistant (MDR) and 22/38 (58%) of extensively drug-resistant (XDR) isolates. Genome-wide polymorphisms identified using whole-genome sequencing were used in a phylogenetically-aware linear mixed model to identify polymorphisms associated with amoxicillin/clavulanate susceptibility. Susceptibility to amoxicillin/clavulanate was over-represented among isolates within a specific clade (LAM4), in particular among XDR strains. Twelve sets of polymorphisms were identified as putative markers of amoxicillin/clavulanate susceptibility, five of which were confined solely to LAM4. Within the LAM4 clade, ‘paradoxical hypersusceptibility’ to amoxicillin/clavulanate has evolved in parallel to first and second-line drug resistance. Given the high prevalence of LAM4 among XDR TB in South Africa, our data support an expanded role for β-lactam/β-lactamase inhibitor combinations for treatment of drug-resistant M. tuberculosis.

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KW - Beta-lactam antibiotics

KW - Extensively drug resistant (XDR)

KW - Multi-drug resistant (MDR)

KW - pks12

KW - Recombination

KW - tuberculosis

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