Spiropiperidyl rifabutins: expanded in vitro testing against ESKAPE pathogens and select bacterial biofilms

Cabal, María‐Paz; Long, Timothy E.; Turos, Edward; García, Ana-Belén; Allen, Jessie L; Budny, Bridget G.; Shaw, Lindsey N.

doi:10.1038/s41429-020-0346-x

Cited by 3 publications

(2 citation statements)

References 20 publications

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“…The success of RMP in the treatment of tuberculosis has demonstrated that compounds inhibiting transcription can effectively disrupt proliferation of mycobacteria. Moreover, considering the activity of rifamycins on intracellular bacteria and biofilms, discovery or modification of rifamycins with activity against NTM has attracted renewed interest ( 1 , 48 , 49 ). Here, we showed that modification of the C25 position of rifamycin S by cross-linking via an imidazole carbamate active intermediate and the secondary amine 4-(benzylamino)-1-piperidine leads to improved antimicrobial activity of rifamycin S analogs against RGM, including clinical Mab isolates.…”

Section: Discussionmentioning

confidence: 99%

C25-modified rifamycin derivatives with improved activity against Mycobacterium abscessus

et al. 2022

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Infections caused by Mycobacterium abscessus are difficult to treat due to its intrinsic resistance to most antibiotics. Formation of biofilms and the capacity of M. abscessus to survive inside host phagocytes further complicate eradication. Herein, we explored whether addition of a carbamate-linked group at the C25 position of rifamycin SV blocks enzymatic inactivation by ArrMab, an ADP-ribosyltransferase conferring resistance to rifampicin. Unlike rifampicin, 5j, a benzyl piperidine rifamycin derivative with a morpholino substituted C3 position and a naphthoquinone core, is not modified by purified ArrMab. Additionally, we show that the ArrMab D82 residue is essential for catalytic activity. Thermal profiling of ArrMab in the presence of 5j, rifampicin or rifabutin shows that 5j does not bind to ArrMab. We found that the activity of 5j is comparable to amikacin against M. abscessus planktonic cultures and pellicles. Critically, 5j also exerts potent antimicrobial activity against M. abscessus in human macrophages and shows synergistic activity with amikacin and azithromycin.

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Section: Discussionmentioning

confidence: 99%

C25-modified rifamycin derivatives with improved activity against Mycobacterium abscessus

et al. 2022

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“…250 Twenty-four novel spiropiperidyl rifabutin derivatives (rifastures) were tested in vitro against an ESKAPE panel, where 13 of the compounds showed promising antibacterial activities against MRSA, vancomycin-resistant S. aureus (VRSA), and vancomycin-resistant enterococci (VRE) strains (MIC < 1 μg mL −1 ; ∼1.18 μM). 251 In a recent study, Nong et al isolated 14 ansamycin derivatives from marine derived Streptomyces sp. SCSGAA 0027.…”

Section: Characterized Target Sites Of Rnap and Respective Inhibitorsmentioning

confidence: 99%

Beyond the approved: target sites and inhibitors of bacterial RNA polymerase from bacteria and fungi

2022

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C25-modified rifamycin derivatives with improved activity againstMycobacterium abscessus

Paulowski

Beckham

Johansen

et al. 2021

Preprint

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Infections caused by Mycobacterium abscessus are difficult to treat due to its intrinsic resistance to most antibiotics. Formation of biofilms and the capacity of M. abscessus to survive inside host phagocytes further complicate eradication. Herein, we explored whether addition of a carbamate-linked group at the C25 position of rifamycin SV blocks enzymatic inactivation by ArrMab, an ADP-ribosyltransferase conferring resistance to rifampicin. Unlike rifampicin, 5j, a benzyl piperidine rifamycin derivative with a morpholino substituted C3 position, is not modified by purified ArrMab. Additionally, we show that the ArrMab D82 residue is essential for catalytic activity. Thermal profiling of ArrMab in the presence of 5j, rifampicin or rifabutin shows that 5j does not bind to ArrMab. We found that the activity of 5j is comparable to amikacin against M. abscessus planktonic cultures and pellicles. Critically, 5j also exerts potent antimicrobial activity against M. abscessus in human macrophages and shows synergistic activity with amikacin and azithromycin.

show abstract

Spiropiperidyl rifabutins: expanded in vitro testing against ESKAPE pathogens and select bacterial biofilms

Cited by 3 publications

References 20 publications

C25-modified rifamycin derivatives with improved activity against Mycobacterium abscessus

C25-modified rifamycin derivatives with improved activity against Mycobacterium abscessus

Beyond the approved: target sites and inhibitors of bacterial RNA polymerase from bacteria and fungi

C25-modified rifamycin derivatives with improved activity againstMycobacterium abscessus

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