New C25 carbamate rifamycin derivatives are resistant to inactivation by ADP-ribosyl transferases

Combrink, Keith D.; Denton, Daniel; Harran, Susan; Ma, Zhenkun; Chapo, Katrina; Yan, Dalai; Bonventre, Eric J.; Roche, Eric; Doyle, Timothy B; Robertson, Gregory T.; Lynch, A. Simon

doi:10.1016/j.bmcl.2006.10.016

Cited by 32 publications

(36 citation statements)

References 19 publications

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“…Understanding the mechanistic basis of the activity differences may open new avenues to inform medicinal chemistry efforts and discover more potent rifamycins for the treatment of mycobacterial infections. Interestingly, Rominski and colleagues (50) recently showed via elegant genetic studies, including heterologous expression and gene knockout studies, that MAB_0591 , encoding a putative rifampin ADP-ribosyltransferase (48, 51–53), is a major contributor to the high level of intrinsic rifampin resistance in M. abscessus subsp.…”

Section: Discussionmentioning

confidence: 99%

Rifabutin Is Active against Mycobacterium abscessus Complex

Aziz

Low

et al. 2017

Antimicrob Agents Chemother

125

158

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Lung infections caused by Mycobacterium abscessus are emerging as a global threat to individuals with cystic fibrosis and to other patient groups. Recent evidence for human-to-human transmission worsens the situation. M. abscessus is an intrinsically multidrug-resistant pathogen showing resistance to even standard antituberculosis drugs, such as rifampin. Here, our objective was to identify existing drugs that may be employed for the treatment of M. abscessus lung disease. A collection of more than 2,700 approved drugs was screened at a single-point concentration against an M. abscessus clinical isolate. Hits were confirmed with fresh solids in dose-response experiments. For the most attractive hit, growth inhibition and bactericidal activities against reference strains of the three M. abscessus subspecies and a collection of clinical isolates were determined. Surprisingly, the rifampin derivative rifabutin had MICs of 3 ± 2 μM (3 μg/ml) against the screening strain, the reference strains M. abscessus subsp. abscessus ATCC 19977, M. abscessus subsp. bolletii CCUG 50184-T, and M. abscessus subsp. massiliense CCUG 48898-T, as well as against a collection of clinical isolates. Furthermore, rifabutin was active against clarithromycin-resistant strains. In conclusion, rifabutin, in contrast to rifampin, is active against the Mycobacterium abscessus complex bacteria in vitro and may be considered for treatment of M. abscessus lung disease.

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Section: Discussionmentioning

confidence: 99%

Rifabutin Is Active against Mycobacterium abscessus Complex

Aziz

Low

et al. 2017

Antimicrob Agents Chemother

125

158

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“…Recently, new rifamycins with carbamate derivatization at position 25 have been reported that maintain antibiotic activity in the presence of Arr (38). The crystal structure of rifampin bound to Arr-ms provides the logic for evasion of inactivation by these new compounds because the bulky carbamate derivatives reported would be unable to bind productively to the enzyme, thereby avoiding modification.…”

Section: Resultsmentioning

confidence: 99%

“…The 3D structure and function studies presented here provide the molecular rationale for strategies to overcome Arr such as through alteration of the ansa-bridge of the antibiotic (e.g., ref. 38) and the development of Arr inhibitors that have the potential to overcome this threat to the next generations of rifamycin antibiotics. Furthermore, this work provides another example of the exploitation of important protein scaffolds by evolution resulting in antibiotic resistance.…”

Section: Resultsmentioning

confidence: 99%

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Rifamycin antibiotic resistance by ADP-ribosylation: Structure and diversity of Arr

Baysarowich

Koteva

Hughes

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

157

184

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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.crystallography ͉ resistome ͉ rifampin ͉ ribosyltransferase

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“…Understanding the molecular interactions between RPH and rifamycin substrates will provide the basis for generating rifamycin analogs that are not susceptible to these enzymes. The possibility of resistance-proof rifamycins has been exemplified with the recent development of C25 carbamate rifamycin derivatives that retain activity against Arr-containing bacteria (46).…”

Section: Discussionmentioning

confidence: 99%

A rifamycin inactivating phosphotransferase family shared by environmental and pathogenic bacteria

Spanogiannopoulos

Waglechner

Koteva

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Environmental microorganisms are a source of diverse antibiotic resistance determinants. With the appropriate selection pressure, these resistance genes can be mobilized to clinically relevant pathogens. Identifying and characterizing elements of the environmental antibiotic resistome provides an early warning of what we may expect to encounter in the clinic. We uncover a conserved genetic element associated with various rifamycin antibiotic-inactivating mechanisms. This element led to the identification of a new resistance gene and associated enzyme responsible for inactivating rifamycin antibiotics by phosphorylation. Cryptic orthologous genes are also found in pathogenic bacteria but remain susceptible to the drug. This study reveals a new antibiotic resistance protein family and the unexpected prevalence of a silent rifamycin resistome among pathogenic bacteria.

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New C25 carbamate rifamycin derivatives are resistant to inactivation by ADP-ribosyl transferases

Cited by 32 publications

References 19 publications

Rifabutin Is Active against Mycobacterium abscessus Complex

Rifabutin Is Active against Mycobacterium abscessus Complex

Rifamycin antibiotic resistance by ADP-ribosylation: Structure and diversity of Arr

A rifamycin inactivating phosphotransferase family shared by environmental and pathogenic bacteria

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