Anthracimycin is a

polyketide Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...

antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...

discovered in 2013. Anthracimycin is derived from marine

actinobacteria The ''Actinomycetota'' (or ''Actinobacteria'') are a phylum of all gram-positive bacteria. They can be terrestrial or aquatic. They are of great economic importance to humans because agriculture and forests depend on their contributions to so ...

. In preliminary laboratory research, it has shown activity against ''

Bacillus anthracis ''Bacillus anthracis'' is a gram-positive and rod-shaped bacterium that causes anthrax, a deadly disease to livestock and, occasionally, to humans. It is the only permanent ( obligate) pathogen within the genus ''Bacillus''. Its infection is a ...

'', the bacteria that causes

anthrax Anthrax is an infection caused by the bacterium ''Bacillus anthracis''. It can occur in four forms: skin, lungs, intestinal, and injection. Symptom onset occurs between one day and more than two months after the infection is contracted. The sk ...

, and against methicillin-resistant ''Staphylococcus aureus'' (MRSA).

Discovery of anthracimycin

Anthracimycin was first isolated from a species of marine ''

Streptomyces ''Streptomyces'' is the largest genus of Actinomycetota and the type genus of the family Streptomycetaceae. Over 500 species of ''Streptomyces'' bacteria have been described. As with the other Actinomycetota, streptomycetes are gram-positive, ...

'' (strain CNH365) which was collected off the shore of Santa Barbara, CA. Another strain of ''

'' (strain T676) isolated off the coast of St. John's Island, Singapore, was found to also produce anthracimycin. This strain was found to contain the biosynthetic gene cluster for anthracimycin production.

Biosynthesis

Anthracimycin is the product of a type I

polyketide synthase Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...

(PKS). This modular synthetic pathway uses a ''trans''-

acyltransferase Acyltransferase is a type of transferase enzyme that acts upon acyl groups. Examples include: * Glyceronephosphate O-acyltransferase * Lecithin-cholesterol acyltransferase *Long-chain-alcohol O-fatty-acyltransferase In enzymology, a long-chain- ...

(AT) domain to load successive units of

malonyl-CoA Malonyl-CoA is a coenzyme A derivative of malonic acid. Functions It plays a key role in chain elongation in fatty acid biosynthesis and polyketide biosynthesis. Fatty acid biosynthesis Malonyl-CoA provides 2-carbon units to fatty acids and commi ...

(MCoA) and

methylmalonyl-CoA Methylmalonyl-CoA is the thioester consisting of coenzyme A linked to methylmalonic acid. It is an important intermediate in the biosynthesis of succinyl-CoA, which plays an essential role in the tricarboxylic acid cycle (aka the Citric Acid Cycle ...

(MMCoA) to build the

macrolide The Macrolides are a class of natural products that consist of a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered. Macrol ...

backbone. The synthesis is composed of 10 biosynthetic modules consisting of the typical domains associated with PKS biosynthetic pathways (See Figure 1). Formation of the

decalin Decalin (decahydronaphthalene, also known as bicyclo .4.0ecane and sometimes decaline), a bicyclic organic compound, is an industrial solvent. A colorless liquid with an aromatic odor, it is used as a solvent for many resins or fuel additives. I ...

ring is part of the PKS pathway and not a post-tailoring event. This occurs via a spontaneous +2cycloaddition after module 8 (See Figure 2). Cyclization to form the larger lactone ring is the final step of the process by the

thioesterase Thioesterases are enzymes which belong to the esterase family. Esterases, in turn, are one type of the several hydrolases known. Thioesterases exhibit esterase activity (splitting of an ester into acid and Alcohol (chemistry), alcohol, in the pres ...

domain.

Antibiotic activity

Anthracimycin was first noted for its potent activity against ''

'' (strain UM23C1-1), which is known to cause the human infectious disease

, with a

minimum inhibitory concentration In microbiology, the minimum inhibitory concentration (MIC) is the lowest concentration of a chemical, usually a drug, which prevents visible growth of a bacterium or bacteria. MIC depends on the microorganism, the affected human being (in vivo onl ...

(MIC) of 0.031 ug/mL. It was also initially found to have activity against other

Gram-positive In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. Gram-positive bacte ...

genera such as staphylococci, enterococci, and streptococci, but was not active against

Gram-negative Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wall ...

strains. In a follow-up study, anthracimycin was screened against a panel of ''

Staphylococcus aureus ''Staphylococcus aureus'' is a Gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often positive ...

'' strains both ''in vivo'' and ''in vitro.'' All strains of ''S. aureus'' tested were susceptible to anthracimycin at MIC values of less than or equal to 0.25 mg/L. This included strains of methicillin-susceptible, methicillin-resistant (MRSA), and vancomycin-resistant strains. Unfortunately, postantibiotic effects were minimal and the effects of the antibiotic were mitigated by presence of 20% human serum. Nevertheless, levels of anthracimycin significantly below the MIC were still able to slow MRSA growth. The compound was found to be minimally toxic to human cells with an

IC50 The half maximal inhibitory concentration (IC50) is a measure of the potency of a substance in inhibiting a specific biological or biochemical function. IC50 is a quantitative measure that indicates how much of a particular inhibitory substance ...

of 70 mg/L against human carcinoma cells. It has been found that the most likely mechanism of action for anthracimycin is inhibition of RNA and DNA synthesis, but not through DNA intercalation. As part of an ''in vivo'' study with a murine peritonitis model of infection, anthracimycin was found to protect mice against mortality by MRSA at doses of 1 and 10 mg/kg. As a result, anthracimycin is a promising new scaffold for development of novel antibiotics against MRSA.

References

{{reflist Macrolide antibiotics