Malacidin A

Identification

Name

Malacidin A

Accession Number

DB14051

Description

Malacidin A, along with Malacidin B, is a member of a class of chemicals made by bacteria found in soil that can kill Gram-positive bacteria ¹. Malacidins are 10-member macrocycle lipopeptides discovered via gene sequencing and bioinformatic analysis. While structurally similar to other macrocycle drugs like Daptomycin and Friulimicin B, Malacidin A appears to act via its own distinct mechanism.

Type

Small Molecule

Groups

Experimental

Structure

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MOLSDFPDBSMILESInChI

Similar Structures

Structure for Malacidin A (DB14051)

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Weight

Average: 1249.384
Monoisotopic: 1248.623783282

Chemical Formula

C₅₆H₈₈N₁₂O₂₀

Synonyms

Not Available

Pharmacology

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Indication

Malacidin A is being investigated for its antibiotic action and has potential for use as an antibacterial agent in the future ¹.

Contraindications & Blackbox Warnings

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Pharmacodynamics

Malacidin A disrupts bacterial cell wall synthesis likely leading to cell death in Gram-positive bacteria ¹. This bactericidal effect reduces the number of live bacteria present during infection. Malacidin A has exhibited broad spectrum activity against Gram-positive bacteria including several multi-drug resistant pathogens.

Mechanism of action

Malacidin A appears to bind Lipid II via a calcium dependent mechanism despite the absence of the typical Asp-X-Asp-Gly motif associate with calcium binding. The structure of Malacidin A includes a 3-hydroxy-aspartate residue while the "X" variable spacer residue is absent. It is unknown how these unique structural features may impact the drug's mechanism of action. The binding of Malacidin A to Lipid II prevents the incorporation of the subunit into the cell wall, disrupting synthesis and likely resulting in death of the bacterial cell. Malacidin A does not appear to form pores nor does it seem to integrate into the cell wall. While this mechanism is similar to that of Vancomycin, Malacidin A retains its activity against Vancomycin-resistant pathogens. Unlike other antibiotic agents, Malacidin A also retains its activity in the presence of pulmonary surfactants.

Target	Actions	Organism
ANAM/NAG peptide subunits of peptidoglycan	ligand	Gram positive bacteria

Absorption

Not Available

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

Not Available

Route of elimination

Not Available

Half-life

Not Available

Clearance

Not Available

Adverse Effects

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Toxicity

Malacidin A has no observed toxicity or haemolytic effect on mammalian cells at concentrations of up to 100-250 μg/mL, over 100 times the MIC for affected pathogens ¹.

Affected organisms

Not Available

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Acenocoumarol	The risk or severity of bleeding can be increased when Malacidin A is combined with Acenocoumarol.
BCG vaccine	The therapeutic efficacy of BCG vaccine can be decreased when used in combination with Malacidin A.
Dicoumarol	The risk or severity of bleeding can be increased when Malacidin A is combined with Dicoumarol.
Fluindione	The risk or severity of bleeding can be increased when Malacidin A is combined with Fluindione.
Lactulose	The therapeutic efficacy of Lactulose can be decreased when used in combination with Malacidin A.
Phenindione	The risk or severity of bleeding can be increased when Malacidin A is combined with Phenindione.
Phenprocoumon	The risk or severity of bleeding can be increased when Malacidin A is combined with Phenprocoumon.
Picosulfuric acid	The therapeutic efficacy of Picosulfuric acid can be decreased when used in combination with Malacidin A.
Typhoid vaccine	The therapeutic efficacy of Typhoid vaccine can be decreased when used in combination with Malacidin A.
Vibrio cholerae CVD 103-HgR strain live antigen	The therapeutic efficacy of Vibrio cholerae CVD 103-HgR strain live antigen can be decreased when used in combination with Malacidin A.

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Food Interactions

Not Available

Categories

Drug Categories

• Amino Acids, Peptides, and Proteins
• Anti-Bacterial Agents
• Anti-Infective Agents
• Lipids
• Malacidins
• Peptides

Classification

Not classified

Chemical Identifiers

UNII

Not Available

CAS number

Not Available

InChI Key

USNOUEMKNKRWQT-ORRWAHHJSA-N

InChI

InChI=1S/C56H88N12O20/c1-25(2)17-13-11-12-14-19-35(69)62-40(29(8)54(83)84)50(79)66-42-31(10)59-47(76)34-21-28(7)24-68(34)53(82)39(27(5)6)65-49(78)41(30(9)55(85)86)63-36(70)23-58-45(74)33(22-37(71)72)61-52(81)43(44(73)56(87)88)67-46(75)32(18-15-16-20-57)60-48(77)38(26(3)4)64-51(42)80/h11-12,14,19,25-34,38-44,73H,13,15-18,20-24,57H2,1-10H3,(H,58,74)(H,59,76)(H,60,77)(H,61,81)(H,62,69)(H,63,70)(H,64,80)(H,65,78)(H,66,79)(H,67,75)(H,71,72)(H,83,84)(H,85,86)(H,87,88)/b12-11-,19-14+/t28-,29?,30?,31?,32+,33+,34+,38-,39+,40+,41-,42+,43+,44?/m1/s1

IUPAC Name

(3S)-3-{[(4S,7R,10S,13S,16S,22R,25S,29R,30aS)-10-(4-aminobutyl)-13-[carboxy(hydroxy)methyl]-22-(1-carboxyethyl)-16-(carboxymethyl)-3,29-dimethyl-1,5,8,11,14,17,20,23,26-nonaoxo-7,25-bis(propan-2-yl)-triacontahydropyrrolo[2,1-c]1,4,7,10,13,16,19,22,25-nonaazacyclooctacosan-4-yl]carbamoyl}-2-methyl-3-[(2E,4Z)-8-methylnona-2,4-dienamido]propanoic acid

SMILES

CC(C)CC\C=C/C=C/C(=O)N[C@@H](C(C)C(O)=O)C(=O)N[C@H]1C(C)NC(=O)[C@@H]2C[C@@H](C)CN2C(=O)[C@@H](NC(=O)[C@H](NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](NC1=O)C(C)C)C(O)C(O)=O)C(C)C(O)=O)C(C)C

References

Synthesis Reference

Hover BM, Kim SH, Katz M, et al. Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant Gram-positive pathogens. Nat Microbiol. 2018;3(4):415-422.

General References

1. Hover BM, Kim SH, Katz M, Charlop-Powers Z, Owen JG, Ternei MA, Maniko J, Estrela AB, Molina H, Park S, Perlin DS, Brady SF: Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant Gram-positive pathogens. Nat Microbiol. 2018 Apr;3(4):415-422. doi: 10.1038/s41564-018-0110-1. Epub 2018 Feb 12. [PubMed:29434326]

External Links

ChEBI

140173

Wikipedia

Malacidin

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Not Available

Prices

Not Available

Patents

Not Available

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.0197 mg/mL	ALOGPS
logP	0.39	ALOGPS
logP	-6	ChemAxon
logS	-4.8	ALOGPS
pKa (Strongest Acidic)	2.8	ChemAxon
pKa (Strongest Basic)	10.18	ChemAxon
Physiological Charge	-3	ChemAxon
Hydrogen Acceptor Count	21	ChemAxon
Hydrogen Donor Count	16	ChemAxon
Polar Surface Area	506.76 Å2	ChemAxon
Rotatable Bond Count	22	ChemAxon
Refractivity	306.63 m3·mol-1	ChemAxon
Polarizability	127.11 Å3	ChemAxon
Number of Rings	2	ChemAxon
Bioavailability	0	ChemAxon
Rule of Five	No	ChemAxon
Ghose Filter	No	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	No	ChemAxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Not Available

Targets

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1. NAM/NAG peptide subunits of peptidoglycan

Kind

Group

Organism

Gram positive bacteria

Pharmacological action

Yes

Actions

Ligand

References

1. Hover BM, Kim SH, Katz M, Charlop-Powers Z, Owen JG, Ternei MA, Maniko J, Estrela AB, Molina H, Park S, Perlin DS, Brady SF: Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant Gram-positive pathogens. Nat Microbiol. 2018 Apr;3(4):415-422. doi: 10.1038/s41564-018-0110-1. Epub 2018 Feb 12. [PubMed:29434326]

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Drug created on June 11, 2018 15:46 / Updated on June 12, 2020 16:53