Resistance to d-Cycloserine in the Tubercle Bacilli: Mutation Rate and Transport of Alanine in Parental Cells and Drug-Resistant Mutants

David, Hugo L.

doi:10.1128/aem.21.5.888-892.1971

Cited by 26 publications

(14 citation statements)

References 4 publications

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“…Using this approach, we calculated an ultra-low rate of emergence of spontaneous mutations conferring DCS resistance in M. tuberculosis (in the order of 10 −11 mutations per bacterium per cell division, Table 1), and that DCS does not induce mutagenesis. This result is in agreement with the only other report of the mutation rates of DCS with M. tuberculosis 33 . This ultra-low rate of emergence of DCS-resistance mutations is consistent with DCS engaging two lethal targets in M. tuberculosis , Alr and Ddl, and represents an important barrier for the selection of resistance.…”

Section: Resultssupporting

confidence: 94%

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Comparative fitness analysis of D-cycloserine resistant mutants reveals both fitness-neutral and high-fitness cost genotypes

et al. 2019

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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.

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Section: Resultssupporting

confidence: 94%

“…10 −11 ) (ref. 33 and this work). Mutation rate is important, but identifying and understanding potential routes for compensating fitness costs associated with resistance are equally important to evaluate and predict resistance appearance and dynamics in populations 44 .…”

Section: Discussionsupporting

confidence: 64%

Comparative fitness analysis of D-cycloserine resistant mutants reveals both fitness-neutral and high-fitness cost genotypes

et al. 2019

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“…Fluctuation analysis indicates that the frequency of spontaneous mutations conferring DCS resistance in M. tuberculosis is ultra-low (10 -11 ). This result is in agreement with the only other report of the mutation rate of DCS with M. tuberculosis (29). This ultra-low frequency is consistent with DCS engaging two lethal targets in M. tuberculosis, Alr and Ddl, and represents an important barrier for the selection of resistance.…”

Section: Main Textsupporting

confidence: 93%

Antibiotic resistance evasion is explained by rare mutation frequency and not by lack of compensatory mechanisms

Carvalho

Evangelopoulos

Prosser

et al. 2018

Preprint

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Drug resistant infections represent one of the most challenging medical problems of our time. Dcycloserine is an antibiotic used for decades without appearance and dissemination of antibiotic resistant strains, making it an ideal model compound to understand what drives resistance evasion. We investigated why Mycobacterium tuberculosis fails to become resistant to Dcycloserine. 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 mutation frequency associated with D-cycloserine

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“…Evidence suggested that L-homoserine was transported by the former system only. L-Homoserine was found to be a strong competitive inhibitor of both the DAG and LIV transport systems in marine pseudomonad B-16. Systems similar to the alanine-glycine-Dserine-D-cycloserine transport system of E. coli have also been reported in Bacillus megaterium (26), B. subtilis (5), Streptococcus challis (31), and Mycobacterium tuberculosis (9). The system described in B. megaterium also appears to transport AIB.…”

Section: Vol 124 1975mentioning

confidence: 74%

Characterization of neutral amino acid transport in a marine pseudomonad

Fein¹,

MacLeod²

1975

J Bacteriol

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The transport of neutral amino acids in marine pseudomonad B-16 (ATCC 19855) has been investigated. From patterns of competitive inhibition, mutant analysis, and kinetic data, two active transport systems with overlapping substrate specificities were distinguished and characterized. One system (DAG) served glycine, D-alanine, D-serine, and a-aminoisobutyric acid (AIB) and, to a lesser extent, L-alanine and possibly other related neutral D-and L-amino acids. The other system (IXV) showed high stereospecificity for neutral amino acids with the L configuration and served primarily to transport L-leucine, L-isoleucine, i-valine, and L-alanine. This system exhibited low affinity for a-aminoisobutyric acid. Neither system was able to recognize structural analogues with modified a-amino or a-carboxyl groups. The kinetic parameters for L-alanine transport by the DAG and LIV systems were determined with appropriate mutants defective in either system. For L-alanine, K, values of 4.6 x 10-6 and 1.9 x 10-4 M and Vmax values of 6.9 and 20.8 nmol/min per mg of cell dry weight were obtained for transport via the DAG and LIV systems, respectively. a-Aminoisobutyric acid transport heterogeneity was also resolved with the mutants, and K, values of 2.8 x 10-' and 1.4 x 10-' M AIB were obtained for transport via the DAG and LIV systems, respectively. Both systems required Na+ for activity (0.3 M Na+ optimal) and in this regard are distinguished from systems of similar substrate specificity reported in nonmarine bacteria.

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Resistance to d-Cycloserine in the Tubercle Bacilli: Mutation Rate and Transport of Alanine in Parental Cells and Drug-Resistant Mutants

Cited by 26 publications

References 4 publications

Comparative fitness analysis of D-cycloserine resistant mutants reveals both fitness-neutral and high-fitness cost genotypes

Comparative fitness analysis of D-cycloserine resistant mutants reveals both fitness-neutral and high-fitness cost genotypes

Antibiotic resistance evasion is explained by rare mutation frequency and not by lack of compensatory mechanisms

Characterization of neutral amino acid transport in a marine pseudomonad

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