TY - JOUR
T1 - WarA, a remote homolog of NpmA and KamB from Nocardia wallacei, confers broad spectrum aminoglycoside resistance in Nocardia and Mycobacteria
AU - Hershko, Yizhak
AU - Rannon, Ella
AU - Adler, Amos
AU - Burstein, David
AU - Barkan, Daniel
N1 - Publisher Copyright:
© 2024 Elsevier Ltd and International Society of Antimicrobial Chemotherapy
PY - 2024/2
Y1 - 2024/2
N2 - Objectives: Aminoglycoside resistance in bacteria is typically conferred by specific drug-modifying enzymes. Infrequently, such resistance is achieved through 16S ribosomal RNA methyltransferases, such as NpmA and KamB encoded by Escherichia coli and Streptoalloteichus tenebrarius, respectively. These enzymes are not widespread and have not been described in Nocardia species to date. Methods: We report the genomic mining of 18 Nocardia wallacei isolates that were found to be specifically and substantially resistant to amikacin. Results: We identified a gene coding for a protein with very distant homology to NpmA and KamB. However, 3-D modeling revealed that the tertiary structure of these three proteins was highly similar. Cloning and expressing this gene in two susceptible bacteria Nocardia asteroides, and Mycobacterium smegmatis (another Actinobacterium) led to high-level, pan-aminoglycoside resistance in both cases. We named this gene warA (Wallacei Amikacin Resistance A). Conclusions: This is the first description and experimental characterization of a gene of this family in Nocardia, and the first demonstration that such activity could lead to pan-aminoglycoside resistance in Mycobacteria as well. The discovery of this novel gene has important biotechnology and clinical implications.
AB - Objectives: Aminoglycoside resistance in bacteria is typically conferred by specific drug-modifying enzymes. Infrequently, such resistance is achieved through 16S ribosomal RNA methyltransferases, such as NpmA and KamB encoded by Escherichia coli and Streptoalloteichus tenebrarius, respectively. These enzymes are not widespread and have not been described in Nocardia species to date. Methods: We report the genomic mining of 18 Nocardia wallacei isolates that were found to be specifically and substantially resistant to amikacin. Results: We identified a gene coding for a protein with very distant homology to NpmA and KamB. However, 3-D modeling revealed that the tertiary structure of these three proteins was highly similar. Cloning and expressing this gene in two susceptible bacteria Nocardia asteroides, and Mycobacterium smegmatis (another Actinobacterium) led to high-level, pan-aminoglycoside resistance in both cases. We named this gene warA (Wallacei Amikacin Resistance A). Conclusions: This is the first description and experimental characterization of a gene of this family in Nocardia, and the first demonstration that such activity could lead to pan-aminoglycoside resistance in Mycobacteria as well. The discovery of this novel gene has important biotechnology and clinical implications.
KW - 16S rRNA methylation
KW - Amikacin
KW - Aminoglycoside
KW - Antimicrobial resistance
KW - Mycobacteria
KW - Nocardia
UR - http://www.scopus.com/inward/record.url?scp=85183052377&partnerID=8YFLogxK
U2 - 10.1016/j.ijantimicag.2024.107089
DO - 10.1016/j.ijantimicag.2024.107089
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C2 - 38218322
AN - SCOPUS:85183052377
SN - 0924-8579
VL - 63
JO - International Journal of Antimicrobial Agents
JF - International Journal of Antimicrobial Agents
IS - 2
M1 - 107089
ER -