Identification

Name
Malacidin A
Accession Number
DB14051
Type
Small Molecule
Groups
Experimental
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.

Structure
Thumb
Synonyms
Not Available
Categories
UNII
Not Available
CAS number
Not Available
Weight
Average: 1249.384
Monoisotopic: 1248.623783282
Chemical Formula
C56H88N12O20
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

Pharmacology

Indication

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

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.

TargetActionsOrganism
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
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
Not Available
Food Interactions
Not Available

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
Not Available

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
PropertyValueSource
Water Solubility0.0197 mg/mLALOGPS
logP0.39ALOGPS
logP-6ChemAxon
logS-4.8ALOGPS
pKa (Strongest Acidic)2.8ChemAxon
pKa (Strongest Basic)10.18ChemAxon
Physiological Charge-3ChemAxon
Hydrogen Acceptor Count21ChemAxon
Hydrogen Donor Count16ChemAxon
Polar Surface Area506.76 Å2ChemAxon
Rotatable Bond Count22ChemAxon
Refractivity306.63 m3·mol-1ChemAxon
Polarizability127.11 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Classification
Not classified

Targets

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]

Drug created on June 11, 2018 09:46 / Updated on November 02, 2018 07:49