Gardimycin, a new antibiotic from Actionoplanes. I. Description of the producer strain and fermentation studies.

Parenti, Francesco; Pagani, H.; Beretta, G.

doi:10.7164/antibiotics.29.501

Cited by 31 publications

(14 citation statements)

References 2 publications

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“…Biological Activity All the compoundsshowedan antibacterial activity similar to that of actagardine (1). With the exception of compound13, the carboxamides were generally more active than actagardine with MICs2 to 8 times lower than those of the parent compound ( Table 2).…”

Section: Chemistrymentioning

confidence: 97%

Synthesis and biological activity of some amide derivatives of the lantibiotic actagardine.

Malabarba¹,

Pallanza²,

Berti³

et al. 1990

J. Antibiot.

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A series of basic carboxamides of actagardine ( 1) , a lantibiotic possessing good antistreptococcal activity, were synthetized. Some physico-chemical characteristics, in particular charge and lipophilicity, that influence water solubility were determined. The in vitro and in vivo activity was evaluated. The monocarboxamides were generally more active than actagardine against selected Gram-positive bacteria. The 3,3-dimethylamino-l-propylamide hydrochloride (4) showed good water solubility, bactericidal action and favourable antibacterial activity and it appears to be a suitable drug for further investigation.Actagardine (iy~3) is a lanthionine-containing polypeptide antibiotic, belonging to the family of lantibiotics,4) whose structure was recently elucidated.5) It consists of 14 aliphatic amino acids (including one lanthionine and three £-methyllanthionines) and one aromatic (tryptophan) amino acid which generate a polypeptide chain where thioether bridges form four rings. It possesses one acidic function belonging to the glutamic acid side chain (7-COOH). The terminal amino and carboxyl groups belong to the alanine moieties of two £-methyllanthionines. The sequence is shown in Fig. 1. FAB-MSmeasurements5* account for one more oxygen, whoseposition has not yet been established. Actagardine, as well as its related compounddesignated as metabolite D,3) possesses good in vitro activity against Gram-positive bacteria, particularly Streptococci, and obligate anaerobes.3>6) It shows a good in vivo efficacy in experimental Streptococcus pyogenes septicemia in the mouseupon subcutaneous administration and low toxicity (mice, ip). Its mechanismof action consists in the specific inhibition of peptidoglycan biosynthesis in the bacterial cell wall.7) The need to improve the biological properties of actagardine prompted us to prepare some chemical derivatives. As a preliminary approach a series of basic monocarboxamides (2~10) was synthesized. Two diamides (ll and 12) and one iV-acyl derivative (13) were also prepared.

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Section: Chemistrymentioning

confidence: 97%

Synthesis and biological activity of some amide derivatives of the lantibiotic actagardine.

Malabarba¹,

Pallanza²,

Berti³

et al. 1990

J. Antibiot.

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“…In methanol as well as in the crystal, the N terminus folds back in order to interact with the carboxyl group of the glutamic acid residue at position 17. Other lantibiotics that resemble mersacidin with respect to their mode of action are actagardine and ala(0)-actagardine, which are produced by Actinoplanes gabardinensis and Actinoplanes liguriae (23,30). Moreover, with the exception of an exchange of didehydroalanine (Dha) for Ile at position 10 in actagardine and position 16 in mersacidin, the amino acid sequence of the third ring of mersacidin and the second ring of actagardine is conserved and has been suggested to constitute the binding pocket for lipid II (33).…”

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confidence: 99%

Construction of an Expression System for Site-DirectedMutagenesis of the LantibioticMersacidin

Szekat

Jack

Skutlarek

et al. 2003

Appl Environ Microbiol

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The lantibiotic (i.e., lanthionine-containing antibiotic) mersacidin is an antimicrobial peptide of 20 amino acids which is produced by Bacillus sp. strain HIL Y-85,54728. Mersacidin inhibits bacterial cell wall biosynthesis by binding to the precursor molecule lipid II. The structural gene of mersacidin (mrsA) and the genes for the enzymes of the biosynthesis pathway, dedicated transporters, producer self-protection proteins, and regulatory factors are organized in a biosynthetic gene cluster. For site-directed mutagenesis of lantibiotics, the engineered genes must be expressed in an expression system that contains all of the factors necessary for biosynthesis, export, and producer self-protection. In order to express engineered mersacidin peptides, a system in which the engineered gene replaces the wild-type gene on the chromosome was constructed. To test the expression system, three mutants were constructed. In S16I mersacidin, the didehydroalanine residue (Dha) at position 16 was replaced with the Ile residue found in the closely related lantibiotic actagardine. S16I mersacidin was produced only in small amounts. The purified peptide had markedly reduced antimicrobial activity, indicating an essential role for Dha16 in biosynthesis and biological activity of mersacidin. Similarly, Glu17, which is thought to be an essential structure in mersacidin, was exchanged for alanine. E17A mersacidin was obtained in good yields but also showed markedly reduced activity, thus confirming the importance of the carboxylic acid function at position 17 in the biological activity of mersacidin. Finally, the exchange of an aromatic for an aliphatic hydrophobic residue at position 3 resulted in the mutant peptide F3L mersacidin; this peptide showed only moderately reduced activity.

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“…This lantibiotic is produced by Actinoplanes garbadinensis and Actinoplanes liguriae [54][55][56]. It is composed of 19 aa (1890 Da) and four intramolecular rings, one Lan and three MeLan, with the C-terminal MeLan oxidized to sulfoxide [57][58][59].…”

Section: Actagardine and Derivativesmentioning

confidence: 99%

Lantibiotics produced by Actinobacteria and their potential applications (a review)

Gomes¹,

Duarte²,

Bastos³

2017

Microbiology

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The phylum Actinobacteria, which comprises a great variety of Gram-positive bacteria with a high G+C content in their genomes, is known for its large production of bioactive compounds, including those with antimicrobial activity. Among the antimicrobials, bacteriocins, ribosomally synthesized peptides, represent an important arsenal of potential new drugs to face the increasing prevalence of resistance to antibiotics among microbial pathogens. The actinobacterial bacteriocins form a heterogeneous group of substances that is difficult to adapt to most proposed classification schemes. However, recent updates have accommodated efficiently the diversity of bacteriocins produced by this phylum. Among the bacteriocins, the lantibiotics represent a source of new antimicrobials to control infections caused mainly by Gram-positive bacteria and with a low propensity for resistance development. Moreover, some of these compounds have additional biological properties, exhibiting activity against viruses and tumour cells and having also potential to be used in blood pressure or inflammation control and in pain relief. Thus, lantibiotics already described in Actinobacteria exhibit potential practical applications in medical settings, food industry and agriculture, with examples at different stages of pre-clinical and clinical trials.

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Gardimycin, a new antibiotic from Actionoplanes. I. Description of the producer strain and fermentation studies.

Cited by 31 publications

References 2 publications

Synthesis and biological activity of some amide derivatives of the lantibiotic actagardine.

Synthesis and biological activity of some amide derivatives of the lantibiotic actagardine.

Construction of an Expression System for Site-DirectedMutagenesis of the LantibioticMersacidin

Lantibiotics produced by Actinobacteria and their potential applications (a review)

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