Malacidin B

Identification

Generic Name
Malacidin B
DrugBank Accession Number
DB14052
Background

Malacidin B, along with Malacidin A, 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 B appears to act via its own distinct mechanism.

Type
Small Molecule
Groups
Experimental
Structure
Weight
Average: 1263.411
Monoisotopic: 1262.639433346
Chemical Formula
C57H90N12O20
Synonyms
Not Available

Pharmacology

Indication

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

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Contraindications & Blackbox Warnings
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Pharmacodynamics

Malacidin B 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 B has exhibited broad spectrum activity against Gram-positive bacteria including several multi-drug resistant pathogens.

Mechanism of action

Malacidin B 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 B 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 B 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 B 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 B retains its activity against Vancomycin-resistant pathogens. Unlike other antibiotic agents, Malacidin B 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

Adverse Effects
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Toxicity

Malacidin B 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.

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.
DrugInteraction
AcenocoumarolThe risk or severity of bleeding can be increased when Malacidin B is combined with Acenocoumarol.
AmbroxolThe risk or severity of methemoglobinemia can be increased when Malacidin B is combined with Ambroxol.
ArticaineThe risk or severity of methemoglobinemia can be increased when Malacidin B is combined with Articaine.
BCG vaccineThe therapeutic efficacy of BCG vaccine can be decreased when used in combination with Malacidin B.
BenzocaineThe risk or severity of methemoglobinemia can be increased when Malacidin B is combined with Benzocaine.
Food Interactions
Not Available

Categories

Drug Categories
Classification
Not classified
Affected organisms
Not Available

Chemical Identifiers

UNII
Not Available
CAS number
Not Available
InChI Key
SMTCDPMWINUUKC-AVBBYWJWSA-N
InChI
InChI=1S/C57H90N12O20/c1-11-28(6)18-14-12-13-15-20-36(70)63-41(30(8)55(84)85)51(80)67-43-32(10)60-48(77)35-22-29(7)25-69(35)54(83)40(27(4)5)66-50(79)42(31(9)56(86)87)64-37(71)24-59-46(75)34(23-38(72)73)62-53(82)44(45(74)57(88)89)68-47(76)33(19-16-17-21-58)61-49(78)39(26(2)3)65-52(43)81/h12-13,15,20,26-35,39-45,74H,11,14,16-19,21-25,58H2,1-10H3,(H,59,75)(H,60,77)(H,61,78)(H,62,82)(H,63,70)(H,64,71)(H,65,81)(H,66,79)(H,67,80)(H,68,76)(H,72,73)(H,84,85)(H,86,87)(H,88,89)/b13-12-,20-15+/t28?,29-,30?,31?,32?,33+,34+,35+,39-,40+,41+,42-,43+,44+,45?/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-methyldeca-2,4-dienamido]propanoic acid
SMILES
CCC(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. [Article]
ChEBI
140174

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount

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 Solubility0.0167 mg/mLALOGPS
logP0.59ALOGPS
logP-5.6Chemaxon
logS-4.9ALOGPS
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 Count23Chemaxon
Refractivity311.23 m3·mol-1Chemaxon
Polarizability129.37 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
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0002-3390000000-849789d5a59abfbc3756
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0005-0960000000-1ce70157a4549c88b314
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-01bj-2890000000-b800e77f98daf602c557
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-00dm-1900000000-63bae30cacc7811872fa
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-00di-1920000001-12a8b2545d6baa71fb84
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-066u-2930000001-bf2ad95d97006f0298d2
Chromatographic Properties
Collision Cross Sections (CCS)
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. [Article]

Drug created at June 11, 2018 15:49 / Updated at June 12, 2020 16:53