Adaptive laboratory evolution and independent component analysis disentangle complex vancomycin adaptation trajectories
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Adaptive laboratory evolution and independent component analysis disentangle complex vancomycin adaptation trajectories. / Fait, Anaelle; Seif, Yara; Mikkelsen, Kasper; Poudel, Saugat; Wells, Jerry M.; Palsson, Bernhard O.; Ingmer, Hanne.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 119, No. 30, e2118262119, 2022.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Adaptive laboratory evolution and independent component analysis disentangle complex vancomycin adaptation trajectories
AU - Fait, Anaelle
AU - Seif, Yara
AU - Mikkelsen, Kasper
AU - Poudel, Saugat
AU - Wells, Jerry M.
AU - Palsson, Bernhard O.
AU - Ingmer, Hanne
N1 - Publisher Copyright: Copyright © 2022 the Author(s).
PY - 2022
Y1 - 2022
N2 - Human infections with methicillin-resistant Staphylococcus aureus (MRSA) are commonly treated with vancomycin, and strains with decreased susceptibility, designated as vancomycin-intermediate S. aureus (VISA), are associated with treatment failure. Here, we profiled the phenotypic, mutational, and transcriptional landscape of 10 VISA strains adapted by laboratory evolution from one common MRSA ancestor, the USA300 strain JE2. Using functional and independent component analysis, we found that: 1) despite the common genetic background and environmental conditions, the mutational landscape diverged between evolved strains and included mutations previously associated with vancomycin resistance (in vraT, graS, vraFG, walKR, and rpoBCD) as well as novel adaptive mutations (SAUSA300_RS04225, ssaA, pitAR, and sagB); 2) the first wave of mutations affected transcriptional regulators and the second affected genes involved in membrane biosynthesis; 3) expression profiles were predominantly strain-specific except for sceD and lukG, which were the only two genes significantly differentially expressed in all clones; 4) three independent virulence systems (φSa3, SaeR, and T7SS) featured as the most transcriptionally perturbed gene sets across clones; 5) there was a striking variation in oxacillin susceptibility across the evolved lineages (from a 10-fold increase to a 63-fold decrease) that also arose in clinical MRSA isolates exposed to vancomycin and correlated with susceptibility to teichoic acid inhibitors; and 6) constitutive expression of the VraR regulon explained crosssusceptibility, while mutations in walK were associated with cross-resistance. Our results show that adaptation to vancomycin involves a surprising breadth of mutational and transcriptional pathways that affect antibiotic susceptibility and possibly the clinical outcome of infections.
AB - Human infections with methicillin-resistant Staphylococcus aureus (MRSA) are commonly treated with vancomycin, and strains with decreased susceptibility, designated as vancomycin-intermediate S. aureus (VISA), are associated with treatment failure. Here, we profiled the phenotypic, mutational, and transcriptional landscape of 10 VISA strains adapted by laboratory evolution from one common MRSA ancestor, the USA300 strain JE2. Using functional and independent component analysis, we found that: 1) despite the common genetic background and environmental conditions, the mutational landscape diverged between evolved strains and included mutations previously associated with vancomycin resistance (in vraT, graS, vraFG, walKR, and rpoBCD) as well as novel adaptive mutations (SAUSA300_RS04225, ssaA, pitAR, and sagB); 2) the first wave of mutations affected transcriptional regulators and the second affected genes involved in membrane biosynthesis; 3) expression profiles were predominantly strain-specific except for sceD and lukG, which were the only two genes significantly differentially expressed in all clones; 4) three independent virulence systems (φSa3, SaeR, and T7SS) featured as the most transcriptionally perturbed gene sets across clones; 5) there was a striking variation in oxacillin susceptibility across the evolved lineages (from a 10-fold increase to a 63-fold decrease) that also arose in clinical MRSA isolates exposed to vancomycin and correlated with susceptibility to teichoic acid inhibitors; and 6) constitutive expression of the VraR regulon explained crosssusceptibility, while mutations in walK were associated with cross-resistance. Our results show that adaptation to vancomycin involves a surprising breadth of mutational and transcriptional pathways that affect antibiotic susceptibility and possibly the clinical outcome of infections.
KW - adaptive laboratory evolution
KW - Antibiotic resistance
KW - transcriptional regulation
KW - virulence
U2 - 10.1073/pnas.2118262119
DO - 10.1073/pnas.2118262119
M3 - Journal article
C2 - 35858453
AN - SCOPUS:85134550593
VL - 119
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 30
M1 - e2118262119
ER -
ID: 317107722