Treatment history shapes the evolution of complex carbapenem-resistant phenotypes in Klebsiella spp.

Lithgow, T.; Zhou, T.; MCDONALD, M.; Rosas, N.; Wilksch, J.; Barber, J.; Li, J.; Wang, Y.; Sun, Z.; Rocker, A.; Webb, C.; Perlaza-Jimenez, L.; Stubenrauch, C.; Vijaykrishn, D.; Song, J.; Taiaroa, G.; Davies, M. R.; Strugnell, R.; Bao, Q.

doi:10.1101/2022.08.30.505938

bioRxiv · 10.1101/2022.08.30.505938

Treatment history shapes the evolution of complex carbapenem-resistant phenotypes in Klebsiella spp.

Lithgow, T.·Zhou, T.·MCDONALD, M.·Rosas, N.·Wilksch, J.·Barber, J.·Li, J.·Wang, Y.·Sun, Z.·Rocker, A.·Webb, C.·Perlaza-Jimenez, L.·Stubenrauch, C.·Vijaykrishn, D.·Song, J.·Taiaroa, G.·Davies, M. R.·Strugnell, R.·Bao, Q.

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Abstract

Antibiotic resistance is driven by selection, but how a bacterial strains evolutionary history shapes drug-resistance remains an open question. Here we reconstruct the genetic and evolutionary mechanisms of carbapenem resistance in a clinical isolate of Klebsiella. A combination of short and long read sequencing, machine learning, genetic and enzymatic analyses established that this carbapenem-resistant strain carries no carbapenemase-encoding genes. Genetic reconstruction of the resistance phenotype confirmed that two distinct genetic loci are necessary for the strain to acquire carbapenem resistance. Experimental evolution of the carbapenem-resistant strains in growth conditions without the antibiotic revealed that both loci confer a significant cost, and are readily lost by de novo mutation resulting in the rapid evolution of a carbapenem-sensitive phenotype. Thus, historical contingency - a patients treatment history - can shape the evolution of antibiotic resistance and suggests that the strategic combinations of antibiotics could direct the evolution of low-fitness, drug-resistant genotypes.

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Lithgow, T., Zhou, T., MCDONALD, M., Rosas, N., Wilksch, J., Barber, J., Li, J., Wang, Y., Sun, Z., Rocker, A., Webb, C., Perlaza-Jimenez, L., Stubenrauch, C., Vijaykrishn, D., Song, J., Taiaroa, G., Davies, M. R., Strugnell, R., Bao, Q.. 2022-08-30. Treatment history shapes the evolution of complex carbapenem-resistant phenotypes in Klebsiella spp.. https://doi.org/10.1101/2022.08.30.505938

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