Comparative fitness analysis of D-cycloserine resistant mutants reveals both fitness-neutral and high-fitness cost genotypes.
Animals
Antibiotics, Antitubercular
/ pharmacology
Blotting, Western
Cycloserine
/ pharmacology
Drug Resistance, Bacterial
/ genetics
Genotype
Humans
Macrophages
/ drug effects
Mice
Mice, Inbred C57BL
Microbial Sensitivity Tests
Monocytes
/ drug effects
Mutation
/ genetics
Mycobacterium tuberculosis
/ drug effects
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
13 09 2019
13 09 2019
Historique:
received:
01
10
2018
accepted:
16
08
2019
entrez:
15
9
2019
pubmed:
15
9
2019
medline:
31
12
2019
Statut:
epublish
Résumé
Drug resistant infections represent one of the most challenging medical problems of our time. D-cycloserine is an antibiotic used for six decades without significant appearance and dissemination of antibiotic resistant strains, making it an ideal model compound to understand what drives resistance evasion. We therefore investigated why Mycobacterium tuberculosis fails to become resistant to D-cycloserine. To address this question, we employed a combination of bacterial genetics, genomics, biochemistry and fitness analysis in vitro, in macrophages and in mice. Altogether, our results suggest that the ultra-low rate of emergence of D-cycloserine resistance mutations is the dominant biological factor delaying the appearance of clinical resistance to this antibiotic. Furthermore, we also identified potential compensatory mechanisms able to minimize the severe fitness costs of primary D-cycloserine resistance conferring mutations.
Identifiants
pubmed: 31519879
doi: 10.1038/s41467-019-12074-z
pii: 10.1038/s41467-019-12074-z
pmc: PMC6744398
doi:
Substances chimiques
Antibiotics, Antitubercular
0
Cycloserine
95IK5KI84Z
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4177Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Cancer Research UK
ID : FC001060
Pays : United Kingdom
Organisme : Medical Research Council
ID : FC001060
Pays : United Kingdom
Références
Nat Rev Drug Discov. 2007 Jan;6(1):41-55
pubmed: 17159922
Proc Natl Acad Sci U S A. 2018 Apr 10;115(15):E3463-E3470
pubmed: 29581252
Microbiol Mol Biol Rev. 2008 Mar;72(1):126-56, table of contents
pubmed: 18322037
J Antimicrob Chemother. 2018 May 1;73(5):1138-1151
pubmed: 29360989
Lancet Infect Dis. 2010 Sep;10(9):621-9
pubmed: 20797644
Antimicrob Agents Chemother. 2016 Oct 21;60(11):6600-6608
pubmed: 27572408
ACS Med Chem Lett. 2013 Dec 12;4(12):1233-1237
pubmed: 24478820
J Clin Microbiol. 2010 Jan;48(1):229-37
pubmed: 19864480
Dis Chest. 1956 Mar;29(3):241-57
pubmed: 13294011
Antimicrob Agents Chemother. 2009 Oct;53(10):4498-500
pubmed: 19687244
J Bacteriol. 1997 Aug;179(16):5046-55
pubmed: 9260945
Cell Rep. 2013 Nov 27;5(4):1121-31
pubmed: 24268774
Nat Genet. 2016 May;48(5):544-51
pubmed: 27064254
Methods Mol Biol. 1998;101:91-107
pubmed: 9921472
Lancet Infect Dis. 2013 Dec;13(12):1057-98
pubmed: 24252483
Antimicrob Agents Chemother. 2016 Sep 23;60(10):6091-9
pubmed: 27480853
Nat Rev Drug Discov. 2013 May;12(5):371-87
pubmed: 23629505
Nat Genet. 2011 Dec 18;44(1):106-10
pubmed: 22179134
PLoS One. 2012;7(8):e43467
pubmed: 22912881
J Antimicrob Chemother. 2008 Oct;62(4):709-12
pubmed: 18577539
Antimicrob Agents Chemother. 1996 Oct;40(10):2291-5
pubmed: 8891132
Tuberculosis (Edinb). 2014 May;94(3):346-54
pubmed: 24637013
Clin Infect Dis. 2018 Nov 28;67(suppl_3):S308-S316
pubmed: 30496460
Rev Infect Dis. 1988 Jul-Aug;10(4):677-8
pubmed: 3055168
Genetics. 1943 Nov;28(6):491-511
pubmed: 17247100
Front Cell Infect Microbiol. 2017 May 08;7:151
pubmed: 28534009
Nucleic Acids Res. 2010 Sep;38(16):e164
pubmed: 20601685
J Biol Chem. 2004 Oct 8;279(41):42574-83
pubmed: 15292272
Biochemistry. 1991 Feb 26;30(8):2017-21
pubmed: 1998664
Genome Res. 2009 Sep;19(9):1639-45
pubmed: 19541911
ACS Infect Dis. 2016 Sep 9;2(9):616-626
pubmed: 27759369
Appl Microbiol. 1971 May;21(5):888-92
pubmed: 4995732
Antimicrob Agents Chemother. 2017 Nov 22;61(12):
pubmed: 28971867
Antimicrob Agents Chemother. 2015 Aug;59(8):5057-60
pubmed: 26033733
Proc Natl Acad Sci U S A. 2011 Mar 8;108(10):4176-81
pubmed: 21368134
Clin Microbiol Rev. 2014 Jul;27(3):587-613
pubmed: 24982323
Science. 2015 Mar 6;347(6226):1064-6
pubmed: 25745145
Nat Genet. 2018 Feb;50(2):307-316
pubmed: 29358649
Biol Methods Protoc. 2018;3(1):bpy009
pubmed: 30197930
Science. 2006 Jun 30;312(5782):1944-6
pubmed: 16809538
PLoS One. 2013 Dec 06;8(12):e82551
pubmed: 24324807
Cell. 2018 Jan 11;172(1-2):121-134.e14
pubmed: 29307490
Antimicrob Agents Chemother. 2003 May;47(5):1577-83
pubmed: 12709325
J Biol Chem. 1989 Feb 15;264(5):2393-6
pubmed: 2644260
Bioinformatics. 2009 Aug 15;25(16):2078-9
pubmed: 19505943
Lancet Respir Med. 2017 Mar 15;:
pubmed: 28344011
N Engl J Med. 2013 Jul 18;369(3):290-2
pubmed: 23863072
Antimicrob Agents Chemother. 2003 Jan;47(1):283-91
pubmed: 12499203
Int J Tuberc Lung Dis. 2013 Oct;17(10):1257-66
pubmed: 23735593
Biochemistry. 2013 Oct 8;52(40):7145-9
pubmed: 24033232
Lancet Infect Dis. 2016 Feb;16(2):161-8
pubmed: 26603172