Extremely Low Hit Rate in a Diverse Chemical Drug Screen Targeting Mycobacterium abscessus

Malin, Jakob J; Winter, Sandra; Gumpel, Edeltraud van; Plum, Georg; Rybniker, Jan

doi:10.1128/aac.01008-19

Cited by 16 publications

(19 citation statements)

References 28 publications

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“…In this context, high throughput screening has been conducted with M ab using various chemical libraries [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. Unfortunately, there are not many active new drug candidates in either the clinical or discovery phase.…”

Section: Introductionmentioning

confidence: 99%

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A Screening of the MMV Pandemic Response Box Reveals Epetraborole as A New Potent Inhibitor against Mycobacterium abscessus

Kim

Hanh

Heo

et al. 2021

IJMS

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Mycobacterium abscessus is the one of the most feared bacterial respiratory pathogens in the world. Unfortunately, there are many problems with the current M. abscessus therapies available. These problems include misdiagnoses, high drug resistance, poor long-term treatment outcomes, and high costs. Until now, there have only been a few new compounds or drug formulations which are active against M. abscessus, and these are present in preclinical and clinical development only. With that in mind, new and more powerful anti-M. abscessus medicines need to be discovered and developed. In this study, we conducted an in vitro-dual screen against M. abscessus rough (R) and smooth (S) variants using a Pandemic Response Box and identified epetraborole as a new effective candidate for M. abscessus therapy. For further validation, epetraborole showed significant activity against the growth of the M. abscessus wild-type strain, three subspecies, drug-resistant strains and clinical isolates in vitro, while also inhibiting the growth of M. abscessus that reside in macrophages without cytotoxicity. Furthermore, the in vivo efficacy of epetraborole in the zebrafish infection model was greater than that of tigecycline. Thus, we concluded that epetraborole is a potential anti-M. abscessus candidate in the M. abscessus drug search.

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Section: Introductionmentioning

confidence: 99%

“…Unfortunately, there are not many active new drug candidates in either the clinical or discovery phase. This may be due to the extremely low hit rate of chemical drug screens that target M ab [ 6 ]. Even selected hits have not been further developed successfully into clinical trials.…”

Section: Introductionmentioning

confidence: 99%

A Screening of the MMV Pandemic Response Box Reveals Epetraborole as A New Potent Inhibitor against Mycobacterium abscessus

Kim

Hanh

Heo

et al. 2021

IJMS

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show abstract

“…Consequently, treatment options are limited and novel drugs are urgently needed. Unfortunately, M. abscessus drug-screens revealed a low hit rate limiting the development of drugs with a new mode of action (6,7). However, repurposing of existing drugs might offer new treatment options (8).…”

mentioning

confidence: 99%

Rifabutin Is Inactivated by Mycobacterium abscessus Arr

Schäfle

Selchow

Borer

et al. 2021

Antimicrob Agents Chemother

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Mycobacterium abscessus exhibits arr (ADP-ribosyltransferase)-dependent rifampicin (RIF) resistance. In apparent contrast, rifabutin (RBT) has demonstrated promising activity in M. abscessus infection models implying that RBT might not be inactivated by Arr. RBT susceptibility testing of M. abscessus Δarr revealed a strongly decreased minimal inhibitory concentration (MIC). Our findings therefore suggest that the efficacy of RBT might be enhanced by rendering RBT resilient to Arr-dependent modification or by blocking M. abscessus Arr activity.

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“…To make matters worse, there are not many active new drug candidates in clinical phase I studies, even at the discovery level. This may be due to the extremely low hit rate in a chemical drug screen targeting M. abscessus [18][19][20][21][22]. Therefore, identification of any active agent for M. abscessus is urgently required, although the minimum inhibitory concentration (MIC) value is in the micromole range.…”

Section: Discussionmentioning

confidence: 99%

Etamycin as a Novel Mycobacterium abscessus Inhibitor

Hanh

Kim

Park

et al. 2020

IJMS

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The increase in drug-resistant Mycobacterium abscessus, which has become resistant to existing standard-of-care agents, is a major concern, and new antibacterial agents are strongly needed. In this study, we introduced etamycin that showed an excellent activity against M. abscessus. We found that etamycin significantly inhibited the growth of M. abscessus wild-type strain, three subspecies, and clinical isolates in vitro and inhibited the growth of M. abscessus that resides in macrophages without cytotoxicity. Furthermore, the in vivo efficacy of etamycin in the zebrafish (Danio rerio) infection model was greater than that of clarithromycin, which is recommended as the core agent for treating M. abscessus infections. Thus, we concluded that etamycin is a potential anti-M. abscessus candidate for further development as a clinical drug candidate.

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Extremely Low Hit Rate in a Diverse Chemical Drug Screen Targeting Mycobacterium abscessus

Cited by 16 publications

References 28 publications

A Screening of the MMV Pandemic Response Box Reveals Epetraborole as A New Potent Inhibitor against Mycobacterium abscessus

A Screening of the MMV Pandemic Response Box Reveals Epetraborole as A New Potent Inhibitor against Mycobacterium abscessus

Rifabutin Is Inactivated by Mycobacterium abscessus Arr

Etamycin as a Novel Mycobacterium abscessus Inhibitor

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