Structural basis of ABCF-mediated resistance to pleuromutilin, lincosamide, and streptogramin A antibiotics in Gram-positive pathogens

Research output: Contribution to journalArticle

Standard

Structural basis of ABCF-mediated resistance to pleuromutilin, lincosamide, and streptogramin A antibiotics in Gram-positive pathogens. / Crowe-McAuliffe, Caillan; Murina, Victoriia; Turnbull, Kathryn Jane; Kasari, Marje; Mohamad, Merianne; Polte, Christine; Takada, Hiraku; Vaitkevicius, Karolis; Johansson, Jörgen; Ignatova, Zoya; Atkinson, Gemma C.; O’Neill, Alex J.; Hauryliuk, Vasili; Wilson, Daniel N.

In: Nature Communications, Vol. 12, No. 1, 3577, 12.2021.

Research output: Contribution to journalArticle

Harvard

Crowe-McAuliffe, C, Murina, V, Turnbull, KJ, Kasari, M, Mohamad, M, Polte, C, Takada, H, Vaitkevicius, K, Johansson, J, Ignatova, Z, Atkinson, GC, O’Neill, AJ, Hauryliuk, V & Wilson, DN 2021, 'Structural basis of ABCF-mediated resistance to pleuromutilin, lincosamide, and streptogramin A antibiotics in Gram-positive pathogens', Nature Communications, vol. 12, no. 1, 3577. https://doi.org/10.1038/s41467-021-23753-1

APA

Crowe-McAuliffe, C., Murina, V., Turnbull, K. J., Kasari, M., Mohamad, M., Polte, C., Takada, H., Vaitkevicius, K., Johansson, J., Ignatova, Z., Atkinson, G. C., O’Neill, A. J., Hauryliuk, V., & Wilson, D. N. (2021). Structural basis of ABCF-mediated resistance to pleuromutilin, lincosamide, and streptogramin A antibiotics in Gram-positive pathogens. Nature Communications, 12(1), [3577]. https://doi.org/10.1038/s41467-021-23753-1

CBE

Crowe-McAuliffe C, Murina V, Turnbull KJ, Kasari M, Mohamad M, Polte C, Takada H, Vaitkevicius K, Johansson J, Ignatova Z, Atkinson GC, O’Neill AJ, Hauryliuk V, Wilson DN. 2021. Structural basis of ABCF-mediated resistance to pleuromutilin, lincosamide, and streptogramin A antibiotics in Gram-positive pathogens. Nature Communications. 12(1):Article 3577. https://doi.org/10.1038/s41467-021-23753-1

MLA

Vancouver

Author

Crowe-McAuliffe, Caillan ; Murina, Victoriia ; Turnbull, Kathryn Jane ; Kasari, Marje ; Mohamad, Merianne ; Polte, Christine ; Takada, Hiraku ; Vaitkevicius, Karolis ; Johansson, Jörgen ; Ignatova, Zoya ; Atkinson, Gemma C. ; O’Neill, Alex J. ; Hauryliuk, Vasili ; Wilson, Daniel N. / Structural basis of ABCF-mediated resistance to pleuromutilin, lincosamide, and streptogramin A antibiotics in Gram-positive pathogens. In: Nature Communications. 2021 ; Vol. 12, No. 1.

RIS

TY - JOUR

T1 - Structural basis of ABCF-mediated resistance to pleuromutilin, lincosamide, and streptogramin A antibiotics in Gram-positive pathogens

AU - Crowe-McAuliffe, Caillan

AU - Murina, Victoriia

AU - Turnbull, Kathryn Jane

AU - Kasari, Marje

AU - Mohamad, Merianne

AU - Polte, Christine

AU - Takada, Hiraku

AU - Vaitkevicius, Karolis

AU - Johansson, Jörgen

AU - Ignatova, Zoya

AU - Atkinson, Gemma C.

AU - O’Neill, Alex J.

AU - Hauryliuk, Vasili

AU - Wilson, Daniel N.

PY - 2021/12

Y1 - 2021/12

N2 - Target protection proteins confer resistance to the host organism by directly binding to the antibiotic target. One class of such proteins are the antibiotic resistance (ARE) ATP-binding cassette (ABC) proteins of the F-subtype (ARE-ABCFs), which are widely distributed throughout Gram-positive bacteria and bind the ribosome to alleviate translational inhibition from antibiotics that target the large ribosomal subunit. Here, we present single-particle cryo-EM structures of ARE-ABCF-ribosome complexes from three Gram-positive pathogens: Enterococcus faecalis LsaA, Staphylococcus haemolyticus VgaALC and Listeria monocytogenes VgaL. Supported by extensive mutagenesis analysis, these structures enable a general model for antibiotic resistance mediated by these ARE-ABCFs to be proposed. In this model, ABCF binding to the antibiotic-stalled ribosome mediates antibiotic release via mechanistically diverse long-range conformational relays that converge on a few conserved ribosomal RNA nucleotides located at the peptidyltransferase center. These insights are important for the future development of antibiotics that overcome such target protection resistance mechanisms.

AB - Target protection proteins confer resistance to the host organism by directly binding to the antibiotic target. One class of such proteins are the antibiotic resistance (ARE) ATP-binding cassette (ABC) proteins of the F-subtype (ARE-ABCFs), which are widely distributed throughout Gram-positive bacteria and bind the ribosome to alleviate translational inhibition from antibiotics that target the large ribosomal subunit. Here, we present single-particle cryo-EM structures of ARE-ABCF-ribosome complexes from three Gram-positive pathogens: Enterococcus faecalis LsaA, Staphylococcus haemolyticus VgaALC and Listeria monocytogenes VgaL. Supported by extensive mutagenesis analysis, these structures enable a general model for antibiotic resistance mediated by these ARE-ABCFs to be proposed. In this model, ABCF binding to the antibiotic-stalled ribosome mediates antibiotic release via mechanistically diverse long-range conformational relays that converge on a few conserved ribosomal RNA nucleotides located at the peptidyltransferase center. These insights are important for the future development of antibiotics that overcome such target protection resistance mechanisms.

U2 - 10.1038/s41467-021-23753-1

DO - 10.1038/s41467-021-23753-1

M3 - Article

C2 - 34117249

AN - SCOPUS:85107814945

VL - 12

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 3577

ER -