{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T20:27:28Z","timestamp":1793910448552,"version":"4.8.0"},"reference-count":32,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2024,1,17]],"date-time":"2024-01-17T00:00:00Z","timestamp":1705449600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Epetraborole (EBO) is a boron-containing inhibitor of bacterial leucyl-tRNA synthetase, with potent activity against nontuberculous mycobacteria (NTM) and Gram-negative bacteria, including Burkholderia pseudomallei. EBO is being developed for the treatment of NTM lung disease and melioidosis, administered in combination with other therapeutic agents in both diseases. Therefore, EBO and its major circulating metabolite M3 were evaluated in comprehensive drug\u2013drug interaction (DDI) in vitro studies. The CYP inhibitory and substrate potential of EBO and M3 were assessed using hepatic microsomes. Stably transfected cells that expressed individual efflux or uptake transporters were used to determine whether EBO or M3 were substrates or inhibitors for these receptors. Stability studies indicated that EBO is a poor substrate for major CYP enzymes. Neither EBO nor M3 was a potent reversible or time-dependent inhibitor of major CYP enzymes. EBO was not an inducer of CYP1A2 mRNA, while it was a weak inducer of CYP2B6 and CYP3A4. EBO was a substrate only for OCT2. At clinically relevant concentrations, neither EBO nor M3 inhibited major human efflux or uptake transporters. Based on these data, at clinically relevant concentrations of EBO and M3, there is a low risk of victim or perpetrator DDI.<\/jats:p>","DOI":"10.3390\/ph17010120","type":"journal-article","created":{"date-parts":[[2024,1,17]],"date-time":"2024-01-17T07:41:28Z","timestamp":1705477288000},"page":"120","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["In Vitro Evaluation of Drug\u2013Drug Interaction Potential of Epetraborole, a Novel Bacterial Leucyl-tRNA Synthetase Inhibitor"],"prefix":"10.3390","volume":"17","author":[{"given":"Afshin","family":"Shafiee","sequence":"first","affiliation":[{"name":"AN2 Therapeutics Inc., 1800 El Camino Real, Suite D, Menlo Park, CA 94027, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay","family":"Chanda","sequence":"additional","affiliation":[{"name":"AN2 Therapeutics Inc., 1800 El Camino Real, Suite D, Menlo Park, CA 94027, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1128\/AAC.02058-12","article-title":"Discovery of a Novel Class of Boron-Based Antibacterials with Activity against Gram-Negative Bacteria","volume":"57","author":"Hernandez","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"De, K. (2022). Epetraborole, a Novel Bacterial Leucyl-TRNA Synthetase Inhibitor, Demonstrates Potent Efficacy and Improves Efficacy of Standard of Care Regimen against Mycobacterium avium Complex in a Chronic Mouse Lung Infection Model, Oxford University Press.","DOI":"10.1093\/ofid\/ofac492.1334"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e01156-21","DOI":"10.1128\/AAC.01156-21","article-title":"Epetraborole Is Active against Mycobacterium abscessus","volume":"65","author":"Ganapathy","year":"2021","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Kim, T., Hanh, B.-T.-B., Heo, B., Quang, N., Park, Y., Shin, J., Jeon, S., Park, J.-W., Samby, K., and Jang, J. (2021). A Screening of the MMV Pandemic Response Box Reveals Epetraborole as A New Potent Inhibitor against Mycobacterium abscessus. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115936"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Sullivan, J.R., Lupien, A., Kalthoff, E., Hamela, C., Taylor, L., Munro, K.A., Schmeing, T.M., Kremer, L., and Behr, M.A. (2021). Efficacy of Epetraborole against Mycobacterium abscessus Is Increased with Norvaline. PLoS Pathog., 17.","DOI":"10.1101\/2021.06.01.446617"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.ccm.2014.10.002","article-title":"Epidemiology of Human Pulmonary Infection with Nontuberculous Mycobacteria A Review","volume":"36","author":"Prevots","year":"2015","journal-title":"Clin. Chest. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"ciaa241","DOI":"10.1093\/cid\/ciaa1125","article-title":"Treatment of Nontuberculous Mycobacterial Pulmonary Disease: An Official ATS\/ERS\/ESCMID\/IDSA Clinical Practice Guideline: Executive Summary","volume":"71","author":"Daley","year":"2020","journal-title":"Clin. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"i3","DOI":"10.1093\/jac\/dkx311","article-title":"Meta-Analyses and the Evidence Base for Microbial Outcomes in the Treatment of Pulmonary Mycobacterium avium\u2013Intracellulare Complex Disease","volume":"72","author":"Pasipanodya","year":"2017","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"ii1","DOI":"10.1136\/thoraxjnl-2017-210927","article-title":"British Thoracic Society Guidelines for the Management of Non-Tuberculous Mycobacterial Pulmonary Disease (NTM-PD)","volume":"72","author":"Haworth","year":"2017","journal-title":"Thorax"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"ofac492.1357","DOI":"10.1093\/ofid\/ofac492.1357","article-title":"1727. Phase 1b Dose-Ranging Study Demonstrates Tolerability and Pharmacokinetics (PK) of Oral Epetraborole at the Predicted Therapeutic Dosage for Mycobacterium avium Complex (MAC) Lung Disease","volume":"9","author":"Eckburg","year":"2022","journal-title":"Open Forum Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Meumann, E.M., Limmathurotsakul, D., Dunachie, S.J., Wiersinga, W.J., and Currie, B.J. (2023). Burkholderia pseudomallei and Melioidosis. Nat. Rev. Microbiol., 1\u201315.","DOI":"10.1038\/s41579-023-00972-5"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/S0140-6736(89)90768-X","article-title":"Halving of Mortality of Severe Melioidosis by Ceftazidime","volume":"334","author":"White","year":"1989","journal-title":"Lancet"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1378\/chest.101.2.555","article-title":"Ceftazidime Monotherapy for Pulmonary Melioidosis in a Traveler Returning from Thailand","volume":"101","author":"Sauerwein","year":"1992","journal-title":"Chest"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1128\/AAC.48.5.1763-1765.2004","article-title":"Outcomes of Patients with Melioidosis Treated with Meropenem","volume":"48","author":"Cheng","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.4269\/ajtmh.2010.10-0038","article-title":"Increasing Incidence of Human Melioidosis in Northeast Thailand","volume":"82","author":"Limmathurotsakul","year":"2010","journal-title":"Am. J. Tropical. Med. Hyg."},{"key":"ref_16","unstructured":"FDA (2020). In Vitro Drug Interaction Studies\u2014Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions. FDA Guid., 1, 1."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1124\/dmd.112.050153","article-title":"Disposition and metabolism of GSK2251052 in humans: A novel boron-containing antibiotic","volume":"41","author":"Bowers","year":"2013","journal-title":"Drug Metab. Dispos."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"819","DOI":"10.2165\/00003088-200342090-00003","article-title":"Pharmacokinetic Interactions with Rifampicin","volume":"42","author":"Niemi","year":"2003","journal-title":"Clin. Pharmacokinet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1124\/dmd.106.014407","article-title":"The Influence of Macrolide Antibiotics on the Uptake of Organic Anions and Drugs Mediated by OATP1B1 and OATP1B3","volume":"35","author":"Seithel","year":"2007","journal-title":"Drug. Metab. Dispos."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"331","DOI":"10.3109\/00498251003698555","article-title":"IC50-Based Approaches as an Alternative Method for Assessment of Time-Dependent Inhibition of CYP3A4","volume":"40","author":"Burt","year":"2010","journal-title":"Xenobiotica"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.toxlet.2014.06.006","article-title":"Inhibition of Cytochrome P450 by Ethambutol in Human Liver Microsomes","volume":"229","author":"Lee","year":"2014","journal-title":"Toxicol. Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5053","DOI":"10.1128\/AAC.01255-13","article-title":"Interaction of Ethambutol with Human Organic Cation Transporters of the SLC22 Family Indicates Potential for Drug-Drug Interactions during Antituberculosis Therapy","volume":"57","author":"Pan","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"423","DOI":"10.2174\/1389200223666220428081109","article-title":"Interactions between Meropenem and Renal Drug Transporters","volume":"23","author":"Dong","year":"2022","journal-title":"Curr. Drug. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1002\/jps.20536","article-title":"Transport of Drugs in the Kidney by the Human Organic Cation Transporter, OCT2 and Its Genetic Variants","volume":"95","author":"Fujita","year":"2006","journal-title":"J. Pharm. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3334","DOI":"10.1128\/AAC.02483-12","article-title":"Intrapulmonary Pharmacokinetics of GSK2251052 in Healthy Volunteers","volume":"57","author":"Tenero","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_26","unstructured":"(2023, November 08). CT.gov NCT05327803\u2014Study of Epetraborole in Patients with Treatment-Refractory MAC Lung Disease, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05327803?intr=epetraborole&rank=4."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1016\/0006-291X(91)91647-U","article-title":"Correlation between Oral Drug Absorption in Humans and Apparent Drug Permeability Coefficients in Human Intestinal Epithelial (Caco-2) Cells","volume":"175","author":"Artursson","year":"1991","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"E1","DOI":"10.1208\/aapsj080101","article-title":"Current Industrial Practices of Assessing Permeability and P-Glycoprotein Interaction","volume":"8","author":"Balimane","year":"2006","journal-title":"AAPS J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1023\/A:1018972102702","article-title":"Drug Absorption Limited by P-Glycoprotein-Mediated Secretory Drug Transport in Human Intestinal Epithelial Caco-2 Cell Layers","volume":"10","author":"Hunter","year":"1993","journal-title":"Pharm. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1124\/dmd.105.008615","article-title":"In Vitro P-Glycoprotein Inhibition Assays for Assessment of Clinical Drug Interaction Potential of New Drug Candidates: A Recommendation for Probe Substrates","volume":"34","author":"Rautio","year":"2006","journal-title":"Drug. Metab. Dispos."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1517\/17425255.1.2.175","article-title":"Caco-2 Cell Permeability Assays to Measure Drug Absorption","volume":"1","author":"Li","year":"2005","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1124\/dmd.105.005579","article-title":"Automated Assessment of Time-Dependent Inhibition of Human Cytochrome P450 Enzymes Using Liquid Chromatography-Tandem Mass Spectrometry Analysis","volume":"33","author":"Atkinson","year":"2005","journal-title":"Drug. Metab. Dispos."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/17\/1\/120\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:48:42Z","timestamp":1760104122000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/17\/1\/120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,17]]},"references-count":32,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["ph17010120"],"URL":"https:\/\/doi.org\/10.3390\/ph17010120","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,17]]}}}