Liposidomycin, the first reported nucleoside antibiotic inhibitor of peptidoglycan biosynthesis translocase I: The discovery of liposidomycin and related compounds with a perspective on their application to new antibiotics

Kimura, Ken‐ichi

doi:10.1038/s41429-019-0241-5

Cited by 17 publications

(12 citation statements)

References 88 publications

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“…The 3-methylglutaryl in caprazamycin is a unique moiety only found in the closely related liposidomycins, muraminomicins, A-84830A and A-90289A [ 65 , 66 ]. The gene cluster of liposidomycin was identified in S. sp.…”

Section: Discussionmentioning

confidence: 99%

Origin of the 3-methylglutaryl moiety in caprazamycin biosynthesis

et al. 2022

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Background Caprazamycins are liponucleoside antibiotics showing bioactivity against Gram-positive bacteria including clinically relevant Mycobacterium tuberculosis by targeting the bacterial MraY-translocase. Their chemical structure contains a unique 3-methylglutaryl moiety which they only share with the closely related liposidomycins. Although the biosynthesis of caprazamycin is understood to some extent, the origin of 3-methylglutaryl-CoA for caprazamycin biosynthesis remains elusive. Results In this work, we demonstrate two pathways of the heterologous producer Streptomyces coelicolor M1154 capable of supplying 3-methylglutaryl-CoA: One is encoded by the caprazamycin gene cluster itself including the 3-hydroxy-3-methylglutaryl-CoA synthase Cpz5. The second pathway is part of primary metabolism of the host cell and encodes for the leucine/isovalerate utilization pathway (Liu-pathway). We could identify the liu cluster in S. coelicolor M1154 and gene deletions showed that the intermediate 3-methylglutaconyl-CoA is used for 3-methylglutaryl-CoA biosynthesis. This is the first report of this intermediate being hijacked for secondary metabolite biosynthesis. Furthermore, Cpz20 and Cpz25 from the caprazamycin gene cluster were found to be part of a common route after both individual pathways are merged together. Conclusions The unique 3-methylglutaryl moiety in caprazamycin originates both from the caprazamycin gene cluster and the leucine/isovalerate utilization pathway of the heterologous host. Our study enhanced the knowledge on the caprazamycin biosynthesis and points out the importance of primary metabolism of the host cell for biosynthesis of natural products.

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Section: Discussionmentioning

confidence: 99%

Origin of the 3-methylglutaryl moiety in caprazamycin biosynthesis

et al. 2022

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“…It is inhibited by tunicamycin and caprazamycin derivatives, such as CPZEN-45. 39 , 75 Several In-vitro studies revealed that CPZEN-45 is active in replicating and non-replicating bacteria with potent MIC (3 µg/mL). 76 …”

Section: Pg Synthesis Inhibitormentioning

confidence: 99%

Recent Progress in the Development of Novel Mycobacterium Cell Wall Inhibitor to Combat Drug-Resistant Tuberculosis

Belete

2022

Microbiol�Insights

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Despite decades of research in drug development against TB, it is still the leading cause of death due to infectious diseases. The long treatment duration, patient noncompliance coupled with the ability of the tuberculosis bacilli to resist the current drugs increases multidrug-resistant tuberculosis that exacerbates the situation. Identification of novel drug targets is important for the advancement of drug development against Mycobacterium tuberculosis. The development of an effective treatment course that could help us eradicates TB. Hence, we require drugs that could eliminate the bacteria and shorten the treatment duration. This review briefly describes the available data on the peptidoglycan component structural characterization, identification of the metabolic pathway, and the key enzymes involved in the peptidoglycan synthesis, like N-Acetylglucosamine-1-phosphate uridyltransferase, mur enzyme, alanine racemase as well as their inhibition. Besides, this paper also provides studies on mycolic acid and arabinogalactan synthesis and the transport mechanisms that show considerable promise as new targets to develop a new product with their inhibiter.

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“…904 The biology of liposidomycins, which are inhibitors of peptidoglycan biosynthesis translocase I, has been recently reviewed. 905 Clethramycin (275) was isolated from cultures of Streptomyces hygroscopicus TP-A0623 as an inhibitor of pollen tube growth. 906 It should be mentioned that the large majority of sulfated sterols and sterol derivatives has more than one sulfate group.…”

Section: Sulfated Metabolitesmentioning

confidence: 99%