PMID- 34396508
OWN - NLM
STAT- MEDLINE
DCOM- 20220303
LR  - 20220303
IS  - 1097-0290 (Electronic)
IS  - 0006-3592 (Linking)
VI  - 118
IP  - 11
DP  - 2021 Nov
TI  - Fast identification of off-target liabilities in early antibiotic discovery with 
      Fourier-transform infrared spectroscopy.
PG  - 4465-4476
LID - 10.1002/bit.27915 [doi]
AB  - Structural modifications of known antibiotic scaffolds have kept the upper hand 
      on resistance, but we are on the verge of not having antibiotics for many common 
      infections. Mechanism-based discovery assays reveal novelty, exclude off-target 
      liabilities, and guide lead optimization. For that, we developed a fast and 
      automatable protocol using high-throughput Fourier-transform infrared 
      spectroscopy (FTIRS). Metabolic fingerprints of Staphylococcus aureus and 
      Escherichia coli exposed to 35 compounds, dissolved in dimethyl sulfoxide (DMSO) 
      or water, were acquired. Our data analysis pipeline identified biomarkers of 
      off-target effects, optimized spectral preprocessing, and identified the 
      top-performing machine learning algorithms for off-target liabilities and 
      mechanism of action (MOA) identification. Spectral bands with known biochemical 
      associations more often yielded more significant biomarkers of off-target 
      liabilities when bacteria were exposed to compounds dissolved in water than DMSO. 
      Highly discriminative models distinguished compounds with predominant off-target 
      effects from antibiotics with well-defined MOA (AUROC > 0.87, AUPR > 0.79, 
      F1 > 0.81), and from the latter predicted their MOA (AUROC > 0.88, AUPR > 0.70, 
      F1 > 0.70). The compound solvent did not affect predictive models. FTIRS is fast, 
      simple, inexpensive, automatable, and highly effective at predicting MOA and 
      off-target liabilities. As such, FTIRS mechanism-based screening assays can be 
      applied for hit discovery and to guide lead optimization during the early stages 
      of antibiotic discovery.
CI  - (c) 2021 Wiley Periodicals LLC.
FAU - Ribeiro da Cunha, Bernardo
AU  - Ribeiro da Cunha B
AD  - Institute for Bioengineering and Biosciences (iBB), Instituto Superior Tecnico 
      (IST), Universidade de Lisboa (UL), Lisboa, Portugal.
AD  - Area Departamental de Engenharia Quimica (ADEQ), ISEL-Instituto Superior de 
      Engenharia de Lisboa, Instituto Politecnico de Lisboa, Lisboa, Portugal.
FAU - Aleixo, Sandra M
AU  - Aleixo SM
AD  - Area Departamental de Matematica (ADM), ISEL-Instituto Superior de Engenharia de 
      Lisboa, Instituto Politecnico de Lisboa, Lisboa, Portugal.
AD  - Centro de Estatistica e Aplicacoes da Universidade de Lisboa (CEAUL), Faculdade 
      de Ciencias da Universidade de Lisboa, Campo Grande, Lisboa, Portugal.
FAU - Fonseca, Luis P
AU  - Fonseca LP
AD  - Institute for Bioengineering and Biosciences (iBB), Instituto Superior Tecnico 
      (IST), Universidade de Lisboa (UL), Lisboa, Portugal.
FAU - Calado, Cecilia R C
AU  - Calado CRC
AD  - Area Departamental de Engenharia Quimica (ADEQ), ISEL-Instituto Superior de 
      Engenharia de Lisboa, Instituto Politecnico de Lisboa, Lisboa, Portugal.
AD  - CIMOSM, ISEL-Centro de Investigacao em Modelacao e Otimizacao de Sistemas 
      Multifuncionais, Instituto Superior de Engenharia de Lisboa, Lisboa, Portugal.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210820
PL  - United States
TA  - Biotechnol Bioeng
JT  - Biotechnology and bioengineering
JID - 7502021
RN  - 0 (Anti-Bacterial Agents)
SB  - IM
MH  - *Anti-Bacterial Agents/analysis/pharmacology
MH  - Escherichia coli/*growth & development
MH  - *Machine Learning
MH  - Spectroscopy, Fourier Transform Infrared
MH  - Staphylococcus aureus/*growth & development
OTO - NOTNLM
OT  - Fourier-transform infrared spectroscopy (FTIR)
OT  - high-throughput screening
OT  - machine learning
OT  - mechanism of action
OT  - off-target liabilities
EDAT- 2021/08/17 06:00
MHDA- 2022/03/04 06:00
CRDT- 2021/08/16 06:17
PHST- 2021/08/13 00:00 [revised]
PHST- 2021/01/27 00:00 [received]
PHST- 2021/08/13 00:00 [accepted]
PHST- 2021/08/17 06:00 [pubmed]
PHST- 2022/03/04 06:00 [medline]
PHST- 2021/08/16 06:17 [entrez]
AID - 10.1002/bit.27915 [doi]
PST - ppublish
SO  - Biotechnol Bioeng. 2021 Nov;118(11):4465-4476. doi: 10.1002/bit.27915. Epub 2021 
      Aug 20.