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. 2018 Aug 9;8(1):11897.
doi: 10.1038/s41598-018-30429-2.

Bifidobacterium adolescentis is intrinsically resistant to antitubercular drugs

Dhanashree Lokesh  1 , Raman Parkesh  2 , Rajagopal Kammara  3
Affiliations

Bifidobacterium adolescentis is intrinsically resistant to antitubercular drugs

Dhanashree Lokesh et al. Sci Rep. .

Abstract

Multiple mutations in the β subunit of the RNA polymerase (rpoβ) of Mycobacterium tuberculosis (Mtb) are the primary cause of resistance to rifamycin (RIF). In the present study, bifidobacterial rpoβ sequences were analyzed to characterize the mutations that contribute to the development of intrinsic resistance to RIF, isoniazid, streptomycin and pyrazinamide. Sequence variations, which mapped to cassettes 1 and 2 of the rpoβ pocket, are also found in multidrug-resistant Mtb (MDR Mtb). Growth curves in the presence of osmolytes and different concentrations of RIF showed that the bacteria adapted rapidly by shortening the growth curve lag time. Insight into the adapted rpoβ DNA sequences revealed that B. adolescentis harbored mutations both in the RIF pocket and in regions outside the pocket. The minimum inhibitory concentrations (MICs) and mutant prevention concentrations (MPCs) indicated that B. longum, B. adolescentis and B. animalis are resistant to antitubercular drugs. 3D-homology modeling and binding interaction studies using computational docking suggested that mutants had reduced binding affinity towards RIF. RIF-exposed/resistant bacteria exhibited variant protein profiles along with morphological differences, such as elongated and branched cells, surface conversion from rough to smooth, and formation of a concentrating ring.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
RIF resistance of different Bifidobacteria (Bold represents B. adolescentis). (A) 20219: B. longum subspp longum (B) 15837: B. thermoacidophilum subspp thermoacidophilum (C) 20089 (D) 20083: B. adolescentis (E) 20088: B. longum subspp infantis (F) 20213: B. breve (G) 10140: B. animalis subspp. lactis (H) 20105: B. animalis.
Figure 2
Figure 2
(a) Spot assay to understand RIF resistance in B. adolescentis (b). SEM studies (c). Compound microscope of B. adolescentis (d). Protein Profile (e). Resistance in terms of viability.
Figure 3
Figure 3
(a–c) inset SEM of RIF treated cells (Inset (a) 10140, (c) 20083) Arrows in (c) indicate terminal hairy structures.
Figure 4
Figure 4
Mutant Prevention Concentration of various Bifidobacteria.
Figure 5
Figure 5
RIF uptake.
Figure 6
Figure 6
RIF pocket of the Bacteria which were treated with various concentrations (2–100 µg) of RIF was sequenced. Mutations were determined by comparing with the sequence of the untreated sample. Amino acid and its number, nucleotide change and corresponding chromatogram in sense direction are tabulated.
Figure 7
Figure 7
RIF pocket of the Bacteria which were treated with various concentrations (2–100 µg) of RIF was sequenced. Mutations were determined by comparing with the sequence of the untreated sample. Amino acid and its number, nucleotide change and corresponding chromatogram in sense direction are tabulated.
Figure 8
Figure 8
(a) 3D-homology model of rpoβ. (b) 3D-homology model of mutant 1 rpoβ. (c) 3D-homology model of mutant 2 rpoβ.
Figure 9
Figure 9
(a) Docked pose of RIF with wild type rpoβ BIFAA. (b) Docked pose of RIF with mutant 1 rpoβ BIFAA. (c) Docked pose of RIF with mutant 2 rpoβ BIFAA.
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