Characterization of spectinamide 1599 efficacy against different mycobacterial phenotypes.
Hollow fiber infection model
Mycobacterium
Phenotypically tolerant isoform
Spectinamide 1599
Tuberculosis
Journal
Tuberculosis (Edinburgh, Scotland)
ISSN: 1873-281X
Titre abrégé: Tuberculosis (Edinb)
Pays: Scotland
ID NLM: 100971555
Informations de publication
Date de publication:
05 2023
05 2023
Historique:
received:
08
02
2023
revised:
31
03
2023
accepted:
09
04
2023
pmc-release:
01
05
2024
medline:
2
6
2023
pubmed:
1
5
2023
entrez:
30
4
2023
Statut:
ppublish
Résumé
Spectinamides are a novel series of spectinomycin analogs being developed for the treatment of tuberculosis. The preclinical lead spectinamide 1599 is an antituberculosis drug that possesses robust in vivo efficacy, good pharmacokinetic properties, and excellent safety profiles in rodents. In individuals infected with Mycobacterium tuberculosis or Mycobacterium bovis, causative agents of tuberculosis, the host immune system is capable of restraining these mycobacteria within granulomatous lesions. The harsh microenvironmental conditions of these granuloma lead to phenotypic transformation of mycobacteria. Phenotypically transformed bacteria display suboptimal growth, or complete growth arrest and are frequently associated with drug tolerance. Here we quantified the effect of spectinamide 1599 on log-phase and phenotypically tolerant isoforms of Mycobacterium bovis BCG using various in vitro approaches as a first indicator of spectinamide 1599 activity against various mycobacterial isoforms. We also used the hollow fiber infection model to establish time-kill curves and deployed pharmacokinetic/pharmacodynamic modeling to characterize the activity differences of spectinamide 1599 towards the different phenotypic subpopulations. Our results indicate that spectinamide 1599 is more efficacious against log phase bacteria when compared to its activity against other phenotypically tolerant forms such as acid phase bacteria and hypoxic phase bacteria, a behavior similar to the established antituberculosis drug isoniazid.
Identifiants
pubmed: 37120915
pii: S1472-9792(23)00040-9
doi: 10.1016/j.tube.2023.102342
pmc: PMC10247484
mid: NIHMS1896569
pii:
doi:
Substances chimiques
spectinamide 1599
0
Spectinomycin
93AKI1U6QF
Antitubercular Agents
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
102342Subventions
Organisme : NIAID NIH HHS
ID : R01 AI090810
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI120670
Pays : United States
Organisme : NIH HHS
ID : S10 OD016226
Pays : United States
Informations de copyright
Copyright © 2023 Elsevier Ltd. All rights reserved.
Références
J Bacteriol. 2002 Dec;184(24):6760-7
pubmed: 12446625
Nat Med. 2014 Feb;20(2):152-158
pubmed: 24464186
Mol Microbiol. 2002 Feb;43(3):717-31
pubmed: 11929527
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15629-34
pubmed: 16227431
J Lab Physicians. 2011 Jul;3(2):75-9
pubmed: 22219558
mBio. 2011 Jul 12;2(4):e00108-11
pubmed: 21750119
Pharm Res. 1999 Feb;16(2):176-85
pubmed: 10100300
Cell Syst. 2021 Nov 17;12(11):1046-1063.e7
pubmed: 34469743
Tuberculosis (Edinb). 2019 Jan;114:119-122
pubmed: 30711150
Microbiol Spectr. 2017 Jan;5(1):
pubmed: 28233509
Antimicrob Agents Chemother. 2013 Sep;57(9):4134-8
pubmed: 23774429
Antimicrob Agents Chemother. 1996 Oct;40(10):2296-9
pubmed: 8891133
J Antimicrob Chemother. 2017 Mar 1;72(3):770-777
pubmed: 27999020
J Bacteriol. 2005 Mar;187(5):1677-84
pubmed: 15716438
Antimicrob Agents Chemother. 2012 May;56(5):2223-30
pubmed: 22391538
Tubercle. 1982 Jun;63(2):89-98
pubmed: 6758252
Drug Discov Today Technol. 2016 Sep - Dec;21-22:41-49
pubmed: 27978987
Antimicrob Agents Chemother. 2021 Oct 18;65(11):e0174420
pubmed: 34424046
Am Rev Respir Dis. 1968 May;97(5):895-903
pubmed: 5647214
Mol Microbiol. 2011 May;80(3):678-94
pubmed: 21401735
Trends Microbiol. 2019 Nov;27(11):942-953
pubmed: 31324436
Tuberculosis (Edinb). 2009 Sep;89(5):378-85
pubmed: 19748318
Nat Commun. 2021 Jun 21;12(1):3816
pubmed: 34155215
mBio. 2010 Aug 10;1(3):
pubmed: 20802826
FEMS Microbiol Rev. 2012 May;36(3):514-32
pubmed: 22320122
Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7877-82
pubmed: 12788972
Clin Microbiol Rev. 2020 Apr 1;33(3):
pubmed: 32238365
Eur J Pharm Sci. 2019 Jan 15;127:233-239
pubmed: 30419293
J Antimicrob Chemother. 2000 Oct;46(4):565-70
pubmed: 11020253
Microbes Infect. 2012 Nov;14(13):1211-9
pubmed: 22841679
J Antimicrob Chemother. 2016 Apr;71(4):964-74
pubmed: 26702921
ACS Infect Dis. 2017 Jan 13;3(1):72-88
pubmed: 28081607
Pathogens. 2018 Nov 15;7(4):
pubmed: 30445695
J Infect Dis. 2007 Jan 15;195(2):194-201
pubmed: 17191164
Lancet Infect Dis. 2022 Jul;22(7):e191-e196
pubmed: 35248168
Infect Immun. 1996 Jun;64(6):2062-9
pubmed: 8675308
PLoS Pathog. 2012;8(6):e1002769
pubmed: 22737072
J Clin Microbiol. 1994 Jul;32(7):1639-43
pubmed: 7929750
ACS Chem Biol. 2013 Oct 18;8(10):2224-34
pubmed: 23898841
Antimicrob Agents Chemother. 2018 Jul 27;62(8):
pubmed: 29866864
Antimicrob Agents Chemother. 2009 Aug;53(8):3197-204
pubmed: 19451303
Infect Immun. 2007 Jul;75(7):3523-30
pubmed: 17502400
Drugs. 2010 Dec 3;70(17):2201-14
pubmed: 21080738
Antimicrob Agents Chemother. 2005 Feb;49(2):627-31
pubmed: 15673743
Ann Intern Med. 1990 Mar 15;112(6):407-15
pubmed: 2106816
Future Med Chem. 2010 Aug;2(8):1371-83
pubmed: 21426023
Antimicrob Agents Chemother. 1994 Sep;38(9):2054-8
pubmed: 7811018
J Biol Chem. 2012 Aug 10;287(33):27743-52
pubmed: 22648414
Sci Rep. 2015 Sep 14;5:13985
pubmed: 26365087
PLoS One. 2010 Nov 30;5(11):e14159
pubmed: 21152403
Antimicrob Agents Chemother. 2021 Feb 17;65(3):
pubmed: 33361293
Antimicrob Agents Chemother. 2021 Mar 18;65(4):
pubmed: 33558283
ACS Infect Dis. 2021 Oct 8;7(10):2850-2863
pubmed: 34546724
J Clin Microbiol. 2011 Jun;49(6):2380-1
pubmed: 21508153