Isolation and characterization of a new antibiotic, malolactomycin A.

Kobinata, Kimie; Koshino, Hiroyuki; Kusakabe, Hiroo; Kobayashi, Yumiko; Yamaguchi, Isamu; Isono, Kiyoshi; Osada, Hiroyuki

doi:10.7164/antibiotics.46.1912

Cited by 8 publications

(3 citation statements)

References 11 publications

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“…(1) The atom number composed of the lactone ring is less important for their antimicrobial activities [50,66,86] and acute toxicity (Table 4). It is worth noting that 32-membered guanidine-containing polyhydroxyl macrolide TCM-34 shows remarkable antifungal activity (MIC, 1.6 to 3.1 μg/mL), while presents very weak antibacterial activity (MIC, more than 100 μg/mL) [52].…”

Section: Antimicrobial Structure-activity Relationshipmentioning

confidence: 99%

Guanidine-Containing Polyhydroxyl Macrolides: Chemistry, Biology, and Structure-Activity Relationship

Song

Yuan

et al. 2019

Molecules

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Antimicrobial resistance has been seriously threatening human health, and discovering new antimicrobial agents from the natural resource is still an important pathway among various strategies to prevent resistance. Guanidine-containing polyhydroxyl macrolides, containing a polyhydroxyl lactone ring and a guanidyl side chain, can be produced by many actinomycetes and have been proved to possess many bioactivities, especially broad-spectrum antibacterial and antifungal activities. To explore the potential of these compounds to be developed into new antimicrobial agents, a review on their structural diversities, spectroscopic characterizations, bioactivities, acute toxicities, antimicrobial mechanisms, and the structure-activity relationship was first performed based on the summaries and analyses of related publications from 1959 to 2019. A total of 63 guanidine-containing polyhydroxyl macrolides were reported, including 46 prototype compounds isolated from 33 marine and terrestrial actinomycetes and 17 structural derivatives. Combining with their antimicrobial mechanisms, structure-activity relationship analyses indicated that the terminal guanidine group and lactone ring of these compounds are vital for their antibacterial and antifungal activities. Further, based on their bioactivities and toxicity analyses, the discovery of guanidyl side-chain targeting to lipoteichoic acid of Staphylococcus aureus indicated that these compounds have a great potency to be developed into antimicrobial and anti-inflammatory drugs.

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Section: Antimicrobial Structure-activity Relationshipmentioning

confidence: 99%

Guanidine-Containing Polyhydroxyl Macrolides: Chemistry, Biology, and Structure-Activity Relationship

Song

Yuan

et al. 2019

Molecules

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“…Sequence analysis does not reveal any discrete AT proteins in the PLM gene cluster raising an intriguing possibility that AT in module 7 is responsible for malonylation of both the cognate ACP for the elongation process and the C-3 hydroxyl of the resulting extended PLM structure when it is attached to this ACP. We note that other polyketide natural products such as azalomycin F, 14 malolactomycin A, 15 and shurimycins A and B 16 contain malonyl esters and are almost certainly generated by modular PKSs. How these malonyl esters are formed has not been addressed, but it seems likely that there may be a similar malonylation process to that occurring in the PLM pathway.…”

mentioning

confidence: 97%

“…The phoslactomycins (PLMs A-F, Figure 1) and fostriecin belong to a class of phosphorylated polyketides that contain multiple double bonds in the cis form. 5,6 For the PLMs there are three double bonds in the cis form (∆ 12,13 ,∆ 14,15 , ∆ 2,3 ) and one in the trans form (∆ 6,7 ). 7,8 The PLM biosynthetic gene cluster has been cloned and sequenced and shown to encode a modular PKS.…”

mentioning

confidence: 99%

cis-Δ^2,3-Double Bond of Phoslactomycins Is Generated by a Post-PKS Tailoring Enzyme

Palaniappan

Alhamadsheh²,

Reynolds³

2008

J. Am. Chem. Soc.

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The antifungal phoslactomycins (PLM A-F), produced by Streptomyes sp HK803, are structurally unusual in that three of their four double bonds are in the cis form (Δ 12,13 , Δ 14,15 , Δ 2,3 ). The PLM polyketide synthase (PKS) has the predicted dehydratase catalytic domain in modules 1,2 and 5 required for establishing two of these cis double bonds (Δ 12,13 Δ 14,15 ), as well as the only trans Δ 6,7 double bond. By contrast, the formation of the cis Δ 2,3 in the unsaturated lactone moiety of PLMs has presented an enigma because the predicted dehydratase domain in module 7 is absent. Herein, we have demonstrated that the plmT 2 gene product, with no homology to PKS dehydratase domains, is required for efficient formation of the cis Δ 2,3 alkene. A series of new PLM products in which the C3 hydroxyl group is retained, are made in plmT 2 deletion mutants. In all of these cases, however, the hydroxyl group is esterified with malonic acid. These malonylated PLM products are converted to the corresponding cis Δ 2,3 PLM products and acetic acid by a facile base-catalyzed decarboxylative elimination reaction. Complete or partial restoration of natural PLM production in a plmT 2 deletion mutant can be accomplished by plasmid based expression of plmT 2 or fos ORF4 (a homologous gene from the fostriecin biosynthetic gene cluster), respectively. The data indicate that dehydrataseindependent pathways also function in establishment of unsaturated 6-membered lactone moieties in other PKS pathways, and provide the first biosynthetic insights into the possible routes by which unusual malonylated polyketide products are generated.Modular polyketide synthases (PKSs) generate a vast array of structurally diverse natural products with important biological activities. 1 They are responsible for formation of macrolides, the vast majority of which contain one or more double bonds. 2 The majoritiy of other natural produces made by modular PKSs similarly contain some double bonds. In the majority of cases the alkenes in the polyketide product are in the trans form. The formation of these double bonds has been shown to be directly attributed to the presence of a ketoreductasedehydratase (KR-DH) didomain within the appropriate module. 3, 4 These didomains catalyze a 3-keto reduction and subsequent Δ 2,3 elimination reaction with the PKS-tethered 3-ketoacyl polyketide intermediates.The phoslactomycins (PLMs A-F Figure 1) and fostriecin belong to a class of phosphorylated polyketides that contain multiple double bonds in the cis form. 5, 6 For the PLMs there are three double bonds in the cis form (Δ 12,13 , Δ 14,15 , Δ 2,3 ) and one in the trans form (Δ 6,7 ). 7, 8The PLM biosynthetic gene cluster has been cloned and sequenced and shown to encode a modular PKS. 9 Modules 1 and 2 contain the expected dehydratase DH-KR didomain required for formation of the conjugated diene, while module 5 contains a DH-KR domain likely responsible for formation of the trans Δ 6,7 alkene. The KR-DH domains which generate a trans double bond do so via a...

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M

Buckingham¹

1997

Dictionary of Natural Products

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Isolation and characterization of a new antibiotic, malolactomycin A.

Cited by 8 publications

References 11 publications

Guanidine-Containing Polyhydroxyl Macrolides: Chemistry, Biology, and Structure-Activity Relationship

Guanidine-Containing Polyhydroxyl Macrolides: Chemistry, Biology, and Structure-Activity Relationship

cis-Δ^2,3-Double Bond of Phoslactomycins Is Generated by a Post-PKS Tailoring Enzyme

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Isolation and characterization of a new antibiotic, malolactomycin A.

Cited by 8 publications

References 11 publications

Guanidine-Containing Polyhydroxyl Macrolides: Chemistry, Biology, and Structure-Activity Relationship

Guanidine-Containing Polyhydroxyl Macrolides: Chemistry, Biology, and Structure-Activity Relationship

cis-Δ2,3-Double Bond of Phoslactomycins Is Generated by a Post-PKS Tailoring Enzyme

M

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cis-Δ^2,3-Double Bond of Phoslactomycins Is Generated by a Post-PKS Tailoring Enzyme