Rifamycin Antibiotic Resistance by ADP-Ribosylation: Structure and Diversity of Arr

Journal Article · Tue Jan 01 04:00:00 EST 2008 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.0711939105· OSTI ID:980437

Baysarowich, J; Koteva, K; Hughes, D; Ejim, L; Griffiths, E; Zhang, K; Junop, M; Wright, G

The rifamycin antibiotic rifampin is important for the treatment of tuberculosis and infections caused by multidrug-resistant Staphylococcus aureus. Recent iterations of the rifampin core structure have resulted in new drugs and drug candidates for the treatment of a much broader range of infectious diseases. This expanded use of rifamycin antibiotics has the potential to select for increased resistance. One poorly characterized mechanism of resistance is through Arr enzymes that catalyze ADP-ribosylation of rifamycins. We find that genes encoding predicted Arr enzymes are widely distributed in the genomes of pathogenic and nonpathogenic bacteria. Biochemical analysis of three representative Arr enzymes from environmental and pathogenic bacterial sources shows that these have equally efficient drug resistance capacity in vitro and in vivo. The 3D structure of one of these orthologues from Mycobacterium smegmatis was determined and reveals structural homology with ADP-ribosyltransferases important in eukaryotic biology, including poly(ADP-ribose) polymerases (PARPs) and bacterial toxins, despite no significant amino acid sequence homology with these proteins. This work highlights the extent of the rifamycin resistome in microbial genera with the potential to negatively impact the expanded use of this class of antibiotic.

• Research Organization: Brookhaven National Laboratory (BNL) National Synchrotron Light Source
• Sponsoring Organization: Doe - Office Of Science
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 980437
• Report Number(s): BNL--93355-2010-JA
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Vol. 12
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
99 GENERAL AND MISCELLANEOUS
AMINO ACID SEQUENCE
ANTIBIOTICS
BACTERIA
BIOLOGY
CAPACITY
DRUGS
ENZYMES
GENES
IN VITRO
IN VIVO
INFECTIOUS DISEASES
MYCOBACTERIUM
POLYMERASES
POTENTIALS
PROTEINS
RANGE
STAPHYLOCOCCUS
TOXINS
TUBERCULOSIS
national synchrotron light source