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Efflux-mediated resistance to a benzothiadiazol derivative effective against Burkholderia cenocepacia.

Scoffone VC, Ryabova O, Makarov V, Iadarola P, Fumagalli M, Fondi M, Fani R, De Rossi E, Riccardi G, Buroni S - Front Microbiol (2015)

Bottom Line: Here a new compound, belonging to the 2,1,3-benzothiadiazol-5-yl family (10126109), with a bactericidal effect and a minimal inhibitory concentration (MIC) of 8 μg/ml against B. cenocepacia, is described.Indeed, rnd-9 overexpression was confirmed by quantitative reverse transcription PCR, and RND-9 was identified in the membrane fractions of the mutant strains.Moreover, the increase in the MIC values of different drugs in the mutant strains, together with complementation experiments, suggested the involvement of RND-9 in the efflux of 10126109, thus indicating again the central role of efflux transporters in B. cenocepacia drug resistance.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Microbiology, Dipartimento di Biologia e Biotecnologie "Lazzaro Spallanzani," Università degli Studi di Pavia Pavia, Italy.

ABSTRACT
Burkholderia cenocepacia is a major concern for people suffering from cystic fibrosis as it contributes to serious respiratory tract infections. The lack of drugs effective against this opportunistic pathogen, along with the high level of resistance to multiple antibiotics, render the treatment of these infections particularly difficult. Here a new compound, belonging to the 2,1,3-benzothiadiazol-5-yl family (10126109), with a bactericidal effect and a minimal inhibitory concentration (MIC) of 8 μg/ml against B. cenocepacia, is described. The compound is not cytotoxic and effective against B. cenocepacia clinical isolates and members of all the known B. cepacia complex species. Spontaneous mutants resistant to 10126109 were isolated and mutations in the MerR transcriptional regulator BCAM1948 were identified. In this way, a mechanism of resistance to this new molecule was described, which relies on the overexpression of the RND-9 efflux pump. Indeed, rnd-9 overexpression was confirmed by quantitative reverse transcription PCR, and RND-9 was identified in the membrane fractions of the mutant strains. Moreover, the increase in the MIC values of different drugs in the mutant strains, together with complementation experiments, suggested the involvement of RND-9 in the efflux of 10126109, thus indicating again the central role of efflux transporters in B. cenocepacia drug resistance.

No MeSH data available.


Related in: MedlinePlus

Chemical structure of 10126109 compound.
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Figure 1: Chemical structure of 10126109 compound.

Mentions: More than 100 compounds from an in-house collection and shown to be effective against other bacteria were tested for their efficacy against B. cenocepacia J2315. For each compound, the MIC was evaluated through the twofold microdilution method (Martin et al., 2006); only a compound belonging to the 2,1,3-benzothiadiazol-5-yl family (named 10126109, Figure 1), was found to have a promising antibacterial activity, showing a MIC of 8 μg/ml against B. cenocepacia J2315 (Table 1).


Efflux-mediated resistance to a benzothiadiazol derivative effective against Burkholderia cenocepacia.

Scoffone VC, Ryabova O, Makarov V, Iadarola P, Fumagalli M, Fondi M, Fani R, De Rossi E, Riccardi G, Buroni S - Front Microbiol (2015)

Chemical structure of 10126109 compound.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4525489&req=5

Figure 1: Chemical structure of 10126109 compound.
Mentions: More than 100 compounds from an in-house collection and shown to be effective against other bacteria were tested for their efficacy against B. cenocepacia J2315. For each compound, the MIC was evaluated through the twofold microdilution method (Martin et al., 2006); only a compound belonging to the 2,1,3-benzothiadiazol-5-yl family (named 10126109, Figure 1), was found to have a promising antibacterial activity, showing a MIC of 8 μg/ml against B. cenocepacia J2315 (Table 1).

Bottom Line: Here a new compound, belonging to the 2,1,3-benzothiadiazol-5-yl family (10126109), with a bactericidal effect and a minimal inhibitory concentration (MIC) of 8 μg/ml against B. cenocepacia, is described.Indeed, rnd-9 overexpression was confirmed by quantitative reverse transcription PCR, and RND-9 was identified in the membrane fractions of the mutant strains.Moreover, the increase in the MIC values of different drugs in the mutant strains, together with complementation experiments, suggested the involvement of RND-9 in the efflux of 10126109, thus indicating again the central role of efflux transporters in B. cenocepacia drug resistance.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Microbiology, Dipartimento di Biologia e Biotecnologie "Lazzaro Spallanzani," Università degli Studi di Pavia Pavia, Italy.

ABSTRACT
Burkholderia cenocepacia is a major concern for people suffering from cystic fibrosis as it contributes to serious respiratory tract infections. The lack of drugs effective against this opportunistic pathogen, along with the high level of resistance to multiple antibiotics, render the treatment of these infections particularly difficult. Here a new compound, belonging to the 2,1,3-benzothiadiazol-5-yl family (10126109), with a bactericidal effect and a minimal inhibitory concentration (MIC) of 8 μg/ml against B. cenocepacia, is described. The compound is not cytotoxic and effective against B. cenocepacia clinical isolates and members of all the known B. cepacia complex species. Spontaneous mutants resistant to 10126109 were isolated and mutations in the MerR transcriptional regulator BCAM1948 were identified. In this way, a mechanism of resistance to this new molecule was described, which relies on the overexpression of the RND-9 efflux pump. Indeed, rnd-9 overexpression was confirmed by quantitative reverse transcription PCR, and RND-9 was identified in the membrane fractions of the mutant strains. Moreover, the increase in the MIC values of different drugs in the mutant strains, together with complementation experiments, suggested the involvement of RND-9 in the efflux of 10126109, thus indicating again the central role of efflux transporters in B. cenocepacia drug resistance.

No MeSH data available.


Related in: MedlinePlus