Redesign of Rifamycin Antibiotics to Overcome ADP‐Ribosylation‐Mediated Resistance

Abstract

Rifamycin antibiotics are a valuable class of antimicrobials for treating infections by mycobacteria and other persistent bacteria owing to their potent bactericidal activity against replicating and non-replicating pathogens. However, the clinical utility of rifamycins against Mycobacterium abscessus is seriously compromised by a novel resistance mechanism, namely, rifamycin inactivation by ADP-ribosylation. Using a structurebased approach, we rationally redesign rifamycins through strategic modification of the ansa-chain to block ADP-ribosylation while preserving on-target activity. Validated by a combination of biochemical, structural, and microbiological studies, the most potent analogs overcome ADP-ribosylation, restored their intrinsic low nanomolar activity and demonstrated significant in vivo antibacterial efficacy. Further optimization by tuning drug disposition properties afforded a preclinical candidate with remarkable potency and an outstanding pharmacokinetic profile.

Exploring antibiotic resistance mechanisms in Mycobacterium abscessus for enhanced therapeutic approaches

“…Compared to rifabutin, RFB-5 m is 50 times more effective against Mab (Lan et al, 2022;Ganapathy et al, 2023b). Moreover, RFB-5 m was observed to display bactericidal properties against the persisters of Mab in caseum (Lan et al, 2022). RFB-5 m also had strong enhanced potency against all members of the Mab complex, other clinically relevant rapidly and slowly growing NTM, all of which encode Arr and block ADP-ribosylation (Ganapathy et al, 2023b).…”

“…Recently, 25-O-desacetyl-25-O-nicotinoylrifabutin (RFB-5 m), a new rifabutin analogue, overcomes inherent rifamycin resistance caused by Arr ( Ganapathy et al, 2023b ). RFB-5 m prevents enzymatic oxidation by maintaining rifabutin’s naphthoquinone core ( Lan et al, 2022 ; Ganapathy et al, 2023b ). Importantly, RFB-5 m’s unique C25 group prevents Arr Mab ADP-ribosylation ( Lan et al, 2022 ; Ganapathy et al, 2023b ).…”

“…RFB-5 m prevents enzymatic oxidation by maintaining rifabutin’s naphthoquinone core ( Lan et al, 2022 ; Ganapathy et al, 2023b ). Importantly, RFB-5 m’s unique C25 group prevents Arr Mab ADP-ribosylation ( Lan et al, 2022 ; Ganapathy et al, 2023b ). Compared to rifabutin, RFB-5 m is 50 times more effective against Mab ( Lan et al, 2022 ; Ganapathy et al, 2023b ).…”

“…Importantly, RFB-5 m’s unique C25 group prevents Arr Mab ADP-ribosylation ( Lan et al, 2022 ; Ganapathy et al, 2023b ). Compared to rifabutin, RFB-5 m is 50 times more effective against Mab ( Lan et al, 2022 ; Ganapathy et al, 2023b ). Moreover, RFB-5 m was observed to display bactericidal properties against the persisters of Mab in caseum ( Lan et al, 2022 ).…”

Rifampicin has no role in treatment ofMycobacterium aviumcomplex pulmonary disease and bactericidal sterilising drugs are needed: a viewpoint

“…As a longer-term strategy, chemical optimisation of the rifamycins to overcome intrinsic resistance could be considered to rehabilitate the class for the treatment of MAC-PD. This approach has delivered promising preclinical results for Mycobacterium abscessus [ 18 ]. A similar strategy could be applied for other bactericidal drugs, such as fluoroquinolones, suffering from unfavourable MIC distributions in MAC [ 4 ].…”