Comparative fitness analysis of D-cycloserine resistant mutants reveals both fitness-neutral and high-fitness cost genotypes
de, Carvalho, LPS
AffiliationMycobacterial Metabolism and Antibiotic Research Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
MetadataShow full item record
AbstractDrug 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.
CitationEvangelopoulos D, Prosser GA, Rodgers A, Dagg BM, Khatri B, Ho MM, et al. Comparative fitness analysis of D-cycloserine resistant mutants reveals both fitness-neutral and high-fitness cost genotypes. Nat Commun. 2019 Sep 13;10(1):4177.
- Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in D-cycloserine resistance.
- Authors: Desjardins CA, Cohen KA, Munsamy V, Abeel T, Maharaj K, Walker BJ, Shea TP, Almeida DV, Manson AL, Salazar A, Padayatchi N, O'Donnell MR, Mlisana KP, Wortman J, Birren BW, Grosset J, Earl AM, Pym AS
- Issue date: 2016 May
- Role of Alanine Racemase Mutations in Mycobacterium tuberculosis d-Cycloserine Resistance.
- Authors: Nakatani Y, Opel-Reading HK, Merker M, Machado D, Andres S, Kumar SS, Moradigaravand D, Coll F, Perdigão J, Portugal I, Schön T, Nair D, Devi KRU, Kohl TA, Beckert P, Clark TG, Maphalala G, Khumalo D, Diel R, Klaos K, Aung HL, Cook GM, Parkhill J, Peacock SJ, Swaminathan S, Viveiros M, Niemann S, Krause KL, Köser CU
- Issue date: 2017 Dec
- [A preliminary study on the molecular characteristics of D-cycloserine resistance of <i>Mycobacterium tuberculosis</i>].
- Authors: Li C, Li GL, Luo Q, Li SJ, Wang RB, Lou YL, Lyu JX, Wan KL
- Issue date: 2017 Feb 10
- Identification of novel mutations associated with cycloserine resistance in Mycobacterium tuberculosis.
- Authors: Chen J, Zhang S, Cui P, Shi W, Zhang W, Zhang Y
- Issue date: 2017 Dec 1
- A point mutation in cycA partially contributes to the D-cycloserine resistance trait of Mycobacterium bovis BCG vaccine strains.
- Authors: Chen JM, Uplekar S, Gordon SV, Cole ST
- Issue date: 2012