Transcriptomic Responses to Antibiotic Exposure in

Overview

Journal Antimicrob Agents Chemother

Publisher American Society for Microbiology

Specialty Pharmacology

Date 2024 Apr 8

PMID 38587412

Authors

Husain Poonawala

Yu Zhang

Sravya Kuchibhotla

Anna G Green

Daniela Maria Cirillo

Federico Di Marco

Andrea Spitlaeri

Paolo Miotto

Maha R Farhat

Affiliations

Soon will be listed here.

Abstract

Transcriptional responses in bacteria following antibiotic exposure offer insights into antibiotic mechanism of action, bacterial responses, and characterization of antimicrobial resistance. We aimed to define the transcriptional antibiotic response (TAR) in (Mtb) isolates for clinically relevant drugs by pooling and analyzing Mtb microarray and RNA-seq data sets. We generated 99 antibiotic transcription profiles across 17 antibiotics, with 76% of profiles generated using 3-24 hours of antibiotic exposure and 49% within one doubling of the WHO antibiotic critical concentration. TAR genes were time-dependent, and largely specific to the antibiotic mechanism of action. TAR signatures performed well at predicting antibiotic exposure, with the area under the receiver operating curve (AUC) ranging from 0.84-1.00 (TAR <6 hours of antibiotic exposure) and 0.76-1.00 (>6 hours of antibiotic exposure) for upregulated genes and 0.57-0.90 and 0.87-1.00, respectfully, for downregulated genes. This work desmonstrates that transcriptomics allows for the assessment of antibiotic activity in Mtb within 6 hours of exposure.

Citing Articles

Drug-induced differential culturability in diverse strains of Mycobacterium tuberculosis.

March V, Maghradze N, Mchedlishvili K, Avaliani T, Aspindzelashvili R, Avaliani Z Sci Rep. 2025; 15(1):3588.

PMID: 39875469 PMC: 11775088. DOI: 10.1038/s41598-024-85092-7.

Emergence of antibiotic-specific phenotypes during prolonged treatment of mice.

Wynn E, Dide-Agossou C, Al Mubarak R, Rossmassler K, Ektnitphong V, Bauman A Antimicrob Agents Chemother. 2025; 69(2):e0131024.

PMID: 39818957 PMC: 11823617. DOI: 10.1128/aac.01310-24.

Predicting bacterial fitness in Mycobacterium tuberculosis with transcriptional regulatory network-informed interpretable machine learning.

Bustad E, Petry E, Gu O, Griebel B, Rustad T, Sherman D bioRxiv. 2024; .

PMID: 39386570 PMC: 11463588. DOI: 10.1101/2024.09.23.614645.

Emergence of antibiotic-specific phenotypes during prolonged treatment of mice.

Wynn E, Dide-Agossou C, Al Mubarak R, Rossmassler K, Ektnitphong V, Bauman A bioRxiv. 2024; .

PMID: 39229030 PMC: 11370397. DOI: 10.1101/2024.08.20.607990.

References

Ismail N, Omar S, Joseph L, Govender N, Blows L, Ismail F . Defining Bedaquiline Susceptibility, Resistance, Cross-Resistance and Associated Genetic Determinants: A Retrospective Cohort Study. EBioMedicine. 2018; 28:136-142. PMC: 5835552. DOI: 10.1016/j.ebiom.2018.01.005. View

Bhattacharyya R, Bandyopadhyay N, Ma P, Son S, Liu J, He L . Simultaneous detection of genotype and phenotype enables rapid and accurate antibiotic susceptibility determination. Nat Med. 2019; 25(12):1858-1864. PMC: 6930013. DOI: 10.1038/s41591-019-0650-9. View

Boyaci H, Saecker R, Campbell E . Transcription initiation in mycobacteria: a biophysical perspective. Transcription. 2019; 11(2):53-65. PMC: 7549741. DOI: 10.1080/21541264.2019.1707612. View

Tagliani E, Cabibbe A, Miotto P, Borroni E, Toro J, Mansjo M . Diagnostic Performance of the New Version (v2.0) of GenoType MTBDRsl Assay for Detection of Resistance to Fluoroquinolones and Second-Line Injectable Drugs: a Multicenter Study. J Clin Microbiol. 2015; 53(9):2961-9. PMC: 4540937. DOI: 10.1128/JCM.01257-15. View

Wilson M, Derisi J, Kristensen H, Imboden P, Rane S, Brown P . Exploring drug-induced alterations in gene expression in Mycobacterium tuberculosis by microarray hybridization. Proc Natl Acad Sci U S A. 1999; 96(22):12833-8. PMC: 23119. DOI: 10.1073/pnas.96.22.12833. View

Milano A, Pasca M, Provvedi R, Lucarelli A, Manina G, de Jesus Lopes Ribeiro A . Azole resistance in Mycobacterium tuberculosis is mediated by the MmpS5-MmpL5 efflux system. Tuberculosis (Edinb). 2008; 89(1):84-90. DOI: 10.1016/j.tube.2008.08.003. View

Li H, Durbin R . Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25(14):1754-60. PMC: 2705234. DOI: 10.1093/bioinformatics/btp324. View

Boehme C, Nabeta P, Hillemann D, Nicol M, Shenai S, Krapp F . Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med. 2010; 363(11):1005-15. PMC: 2947799. DOI: 10.1056/NEJMoa0907847. View

Barczak A, Gomez J, Kaufmann B, Hinson E, Cosimi L, Borowsky M . RNA signatures allow rapid identification of pathogens and antibiotic susceptibilities. Proc Natl Acad Sci U S A. 2012; 109(16):6217-22. PMC: 3341018. DOI: 10.1073/pnas.1119540109. View

10.

Liao Y, Smyth G, Shi W . featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2013; 30(7):923-30. DOI: 10.1093/bioinformatics/btt656. View

11.

Smollett K, Smith K, Kahramanoglou C, Arnvig K, Buxton R, Davis E . Global analysis of the regulon of the transcriptional repressor LexA, a key component of SOS response in Mycobacterium tuberculosis. J Biol Chem. 2012; 287(26):22004-14. PMC: 3381160. DOI: 10.1074/jbc.M112.357715. View

12.

Waddell S, Stabler R, Laing K, Kremer L, Reynolds R, Besra G . The use of microarray analysis to determine the gene expression profiles of Mycobacterium tuberculosis in response to anti-bacterial compounds. Tuberculosis (Edinb). 2004; 84(3-4):263-74. PMC: 7016511. DOI: 10.1016/j.tube.2003.12.005. View

13.

Colangeli R, Helb D, Sridharan S, Sun J, Varma-Basil M, Hazbon M . The Mycobacterium tuberculosis iniA gene is essential for activity of an efflux pump that confers drug tolerance to both isoniazid and ethambutol. Mol Microbiol. 2005; 55(6):1829-40. DOI: 10.1111/j.1365-2958.2005.04510.x. View

14.

Deb C, Lee C, Dubey V, Daniel J, Abomoelak B, Sirakova T . A novel in vitro multiple-stress dormancy model for Mycobacterium tuberculosis generates a lipid-loaded, drug-tolerant, dormant pathogen. PLoS One. 2009; 4(6):e6077. PMC: 2698117. DOI: 10.1371/journal.pone.0006077. View

15.

Andries K, Villellas C, Coeck N, Thys K, Gevers T, Vranckx L . Acquired resistance of Mycobacterium tuberculosis to bedaquiline. PLoS One. 2014; 9(7):e102135. PMC: 4092087. DOI: 10.1371/journal.pone.0102135. View

16.

Fu L, Shinnick T . Understanding the action of INH on a highly INH-resistant Mycobacterium tuberculosis strain using Genechips. Tuberculosis (Edinb). 2006; 87(1):63-70. DOI: 10.1016/j.tube.2006.04.001. View

17.

Chen M, Doddi A, Royer J, Freschi L, Schito M, Ezewudo M . Beyond multidrug resistance: Leveraging rare variants with machine and statistical learning models in Mycobacterium tuberculosis resistance prediction. EBioMedicine. 2019; 43:356-369. PMC: 6557804. DOI: 10.1016/j.ebiom.2019.04.016. View

18.

Boshoff H, Myers T, Copp B, McNeil M, Wilson M, Barry 3rd C . The transcriptional responses of Mycobacterium tuberculosis to inhibitors of metabolism: novel insights into drug mechanisms of action. J Biol Chem. 2004; 279(38):40174-84. DOI: 10.1074/jbc.M406796200. View

19.

Coscolla M, Copin R, Sutherland J, Gehre F, de Jong B, Owolabi O . M. tuberculosis T Cell Epitope Analysis Reveals Paucity of Antigenic Variation and Identifies Rare Variable TB Antigens. Cell Host Microbe. 2015; 18(5):538-48. PMC: 4758912. DOI: 10.1016/j.chom.2015.10.008. View

20.

Mushtaq K, Sheikh J, Amir M, Khan N, Singh B, Agrewala J . Rv2031c of Mycobacterium tuberculosis: a master regulator of Rv2028-Rv2031 (HspX) operon. Front Microbiol. 2015; 6:351. PMC: 4410610. DOI: 10.3389/fmicb.2015.00351. View