Malacidin

Last updated
Malacidin
Malacidin.svg
Identifiers
3D model (JSmol)
ChEBI
PubChem CID
  • 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?/m0/s1
  • CC(NC([C@@H]1C[C@@H](CN1C([C@H](NC([C@@H](NC(CNC([C@H](NC([C@H](NC([C@H](NC([C@@H](N2)C(C)C)=O)CCCCN)=O)C(C(O)=O)O)=O)CC(O)=O)=O)=O)C(C)C(O)=O)=O)C(C)C)=O)C)=O)[C@@H](NC([C@H](NC(/C=C/C=C\CCC(C)C)=O)C(C)C(O)=O)=O)C2=O
Properties
C56H88N12O20 [1]
Molar mass 1249.384 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Malacidins are a class of chemicals made by bacteria found in soil that can kill Gram-positive bacteria. Their activity appears to be dependent on calcium. The discovery of malacidins was published in 2018. [2]

Contents

The malacidin family were discovered using a new method of soil microbiome screening that does not require cell culturing. [3] This allowed researchers to identify genetic components necessary to produce the chemical. Malacidin A was shown to kill Staphylococcus aureus and other Gram-positive bacteria.

At the time of publication it was not certain if the discovery would lead to any new antibiotic drugs, because large investments of time and money are required to determine whether any drug is safe and effective. [4]

Chemical structure

Malacidins are macrocycle lipopeptides. The 2018 paper described two chemicals in the malacidin family, differing only by a methylene at their lipid tails. [2] Their peptide cores include four non-proteinogenic amino acids. [2] The name "malacidin" is derived from the abbreviation of metagenomic acidic lipopeptide antibiotic and the suffix -cidin. [5]

Mechanism of action

Malacidins appear to take on their active conformation after they bind to calcium; the calcium-bound molecule then appears to bind to lipid II, a bacterial cell wall precursor molecule, leading to destruction of the cell wall and death of the bacteria. [2] [6] Therefore, they would be a new member of the class of calcium-dependent antibiotics. [2] [4] The discovery of malacidins supported the view that the calcium-dependent antibiotics are a larger class than previously thought. [2]

History

Malacidins were discovered by researchers at Rockefeller University, led by Brad Hover and Sean Brady. The group had been looking into antibiotics related to daptomycin and their calcium-dependent nature, but determined that it would be impractical to culture variations in lab conditions. [5] Instead, the team used a genetics approach that was more scalable. They focused on searching for novel biosynthetic gene clusters (BGCs) – genes that are usually expressed together, that bacteria use to make secondary metabolites. To do this, they extracted DNA from around 2,000 soil samples to build metagenomic libraries that captured the genetic diversity of the environmental microbiome. They then designed degenerate primers to amplify genes likely to be similar to the BGC that make daptomycin by using a polymerase chain reaction (PCR) procedure, sequenced the amplified genes, and then used metagenomics to confirm that these genes were indeed likely to be the kind of BGCs they sought. One of the novel BGCs they found was present in around 19% of the screened soil samples but not readily found in cultured microbial collections, so they took that BGC, put it into other host bacteria, and then isolated and analyzed the secondary metabolites. [2] [5] The work was published in Nature Microbiology in February 2018. [2] [7]

Research directions

The approach of screening the soil for useful compounds using genomics has been done by others, and is likely to continue to be pursued as a method to further explore primary metabolites and secondary metabolites made by microorganisms. [4] [8]

As of February 2018, the malacidins had not been tested on humans. At the time of their discovery it was unknown whether the discovery would lead to any new antibiotic drugs; showing that a potential drug is safe and effective takes years of work and millions of dollars, and the scientists said at the time that they had no plans to try to develop a drug based on the work. [4] [8] In the 2018 paper, malacidins were shown to kill only Gram-positive bacteria and not Gram-negative bacteria. [2] [7] They were, however, able to kill multidrug-resistant pathogens, including bacteria resistant to vancomycin in the laboratory, and methicillin-resistant Staphylococcus aureus (MRSA) skin infections in an animal wound model. [2] [7]

Brady, Hover, and two other authors disclosed in the 2018 paper that they had "competing financial interests, as they are employees or consultants of Lodo Therapeutics." [2] Lodo was founded in 2016 out of Brady's laboratory, to discover new chemicals in nature as starting points for drug discovery. [9]

See also

Related Research Articles

Antibiotic Antimicrobial substance active against bacteria

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 such infections. They may either kill or inhibit the growth of bacteria. A limited number of antibiotics also possess antiprotozoal activity. Antibiotics are not effective against viruses such as the common cold or influenza; drugs which inhibit viruses are termed antiviral drugs or antivirals rather than antibiotics.

Ampicillin Antibiotic

Ampicillin is an antibiotic used to prevent and treat a number of bacterial infections, such as respiratory tract infections, urinary tract infections, meningitis, salmonellosis, and endocarditis. It may also be used to prevent group B streptococcal infection in newborns. It is used by mouth, by injection into a muscle, or intravenously. Common side effects include rash, nausea, and diarrhea. It should not be used in people who are allergic to penicillin. Serious side effects may include Clostridium difficile colitis or anaphylaxis. While usable in those with kidney problems, the dose may need to be decreased. Its use during pregnancy and breastfeeding appears to be generally safe.

Penicillin Group of antibiotics derived from Penicillium fungi

Penicillins are a group of antibiotics originally obtained from Penicillium moulds, principally P. chrysogenum and P. rubens. Most penicillins in clinical use are synthesised by P. chrysogenum using deep tank fermentation and then purified. A number of natural penicillins have been discovered, but only two purified compounds are in clinical use: penicillin G and penicillin V. Penicillins were among the first medications to be effective against many bacterial infections caused by staphylococci and streptococci. They are members of the β-lactam antibiotics. They are still widely used today for different bacterial infections, though many types of bacteria have developed resistance following extensive use.

Methicillin Antibiotic medication

Methicillin, also known as meticillin, is a narrow-spectrum β-lactam antibiotic of the penicillin class.

Metagenomics Study of genes found in the environment

Metagenomics is the study of genetic material recovered directly from environmental samples. The broad field may also be referred to as environmental genomics, ecogenomics or community genomics.

Multiple drug resistance (MDR), multidrug resistance or multiresistance is antimicrobial resistance shown by a species of microorganism to at least one antimicrobial drug in three or more antimicrobial categories. Antimicrobial categories are classifications of antimicrobial agents based on their mode of action and specific to target organisms. The MDR types most threatening to public health are MDR bacteria that resist multiple antibiotics; other types include MDR viruses, parasites.

Clavulanic acid Β-lactam molecule used as β-lactamase inhibitor to overcome antibiotic resistance in bacteria

Clavulanic acid is a β-lactam drug that functions as a mechanism-based β-lactamase inhibitor. While not effective by itself as an antibiotic, when combined with penicillin-group antibiotics, it can overcome antibiotic resistance in bacteria that secrete β-lactamase, which otherwise inactivates most penicillins.

Daptomycin Antibiotic

Daptomycin, sold under the brand name Cubicin among others, is a lipopeptide antibiotic used in the treatment of systemic and life-threatening infections caused by Gram-positive organisms.

Tetracycline antibiotics Type of broad-spectrum antibiotic

Tetracyclines are a group of broad-spectrum antibiotic compounds that have a common basic structure and are either isolated directly from several species of Streptomyces bacteria or produced semi-synthetically from those isolated compounds. Tetracycline molecules comprise a linear fused tetracyclic nucleus to which a variety of functional groups are attached. Tetracyclines are named for their four ("tetra-") hydrocarbon rings ("-cycl-") derivation ("-ine"). They are defined as a subclass of polyketides, having an octahydrotetracene-2-carboxamide skeleton and are known as derivatives of polycyclic naphthacene carboxamide. While all tetracyclines have a common structure, they differ from each other by the presence of chloride, methyl, and hydroxyl groups. These modifications do not change their broad antibacterial activity, but do affect pharmacological properties such as half-life and binding to proteins in serum.

Efflux (microbiology) Protein complexes that move compounds, generally toxic, out of bacterial cells

All microorganisms, with a few exceptions, have highly conserved DNA sequences in their genome that are transcribed and translated to efflux pumps. Efflux pumps are capable of moving a variety of different toxic compounds out of cells, such as antibiotics, heavy metals, organic pollutants, plant-produced compounds, quorum sensing signals, bacterial metabolites and neurotransmitters via active efflux, which is vital part for xenobiotic metabolism. This active efflux mechanism is responsible for various types of resistance to bacterial pathogens within bacterial species - the most concerning being antibiotic resistance because microorganisms can have adapted efflux pumps to divert toxins out of the cytoplasm and into extracellular media.

The resistome has been used to describe to two similar yet separate concepts:

Fosfomycin

Fosfomycin, sold under the brand name Monurol among others, is an antibiotic primarily used to treat lower UTI. It is not indicated for kidney infections. Occasionally it is used for prostate infections. It is generally taken by mouth.

A lipopeptide is a molecule consisting of a lipid connected to a peptide. They are able to self-assemble into different structures. Many bacteria produced these molecules as a part of their metabolism, especially those of the genus Bacillus, Pseudomonas and Streptomyces. Certain lipopeptides are used as antibiotics. Other lipopeptides are toll-like receptor agonists. Certain lipopeptides can have strong antifungal and hemolytic activities. It has been demonstrated that their activity is generally linked to interactions with the plasma membrane, and sterol components of the plasma membrane could play a major role in this interaction. It is a general trend that adding a lipid group of a certain length to a lipopeptide will increase its bactericidal activity. Lipopeptides with a higher amount of carbon atoms, for example 14 or 16, in its lipid tail will typically have antibacterial activity as well as anti-fungal activity.

Lactocillin Chemical compound

Lactocillin is a thiopeptide antibiotic which is encoded for and produced by biosynthetic genes clusters in the bacteria Lactobacillus gasseri. Lactocillin was discovered and purified in 2014. Lactobacillus gasseri is one of the four Lactobacillus bacteria found to be most common in the human vaginal microbiome. Due to increasing levels of pathogenic resistance to known antibiotics, novel antibiotics are increasingly valuable. Lactocillin could function as a new antibiotic that could help people fight off infections that are resistant to many other antibiotics.

Teixobactin is a peptide-like secondary metabolite of some species of bacteria, that kills some gram-positive bacteria. It appears to belong to a new class of antibiotics, and harms bacteria by binding to lipid II and lipid III, important precursor molecules for forming the cell wall.

Streptomyces lavendulae is a species of bacteria from the genus Streptomyces. It is isolated from soils globally and is known for its production of medically useful biologically active metabolites. To see a photo of this organism click here.

A proteolipid is a protein covalently linked to lipid molecules, which can be fatty acids, isoprenoids or sterols. The process of such a linkage is known as protein lipidation, and falls into the wider category of acylation and post-translational modification. Proteolipids are abundant in brain tissue, and are also present in many other animal and plant tissues. They are proteins covalenently bound to fatty acid chains, often granting them an interface for interacting with biological membranes. They are not to be confused with lipoproteins, a kind of spherical assembly made up of many molecules of lipids and some apolipoproteins.

Antimicrobial spectrum

The antimicrobial spectrum of an antibiotic means the range of microorganisms it can kill or inhibit. Antibiotics can be divided into broad-spectrum antibiotics, extended-spectrum antibiotics and narrow-spectrum antibiotics based on their spectrum of activity. Detailedly, broad-spectrum antibiotics can kill or inhibit a wide range of microorganisms; extended-spectrum antibiotic can kill or inhibit Gram positive bacteria and some Gram negative bacteria; narrow-spectrum antibiotic can only kill or inhibit limited species of bacteria.

Multidrug-resistant bacteria

Multidrug-resistant bacteria are bacteria that are resistant to three or more classes of antimicrobial drugs. MDR bacteria have seen an increase in prevalence in recent years and pose serious risks to public health. MDR bacteria can be broken into 3 main categories: Gram-positive, Gram-negative, and other (acid-stain). These bacteria employ various adaptations to avoid or mitigate the damage done by antimicrobials. With increased access to modern medicine there has been a sharp increase in the amount of antibiotics consumed. Given the abundant use of antibiotics there has been a considerable increase in the evolution of antimicrobial resistance factors, now outpacing the development of new antibiotics.

References

  1. ↑ "Chemical Identifier Resolver". CADD Group Chemoinformatics Tools and User Services. National Cancer Institute.
  2. 1 2 3 4 5 6 7 8 9 10 11 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 (February 2018). "Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant Gram-positive pathogens". Nature Microbiology. 3 (4): 415–422. doi:10.1038/s41564-018-0110-1. PMC   5874163 . PMID   29434326. Open Access logo PLoS transparent.svg
  3. ↑ Borman S (February 19, 2018). "Genetic screen of soil microbes uncovers novel antibiotics: Method could help researchers discover new natural products from hard-to-culture microorganisms". Chemical & Engineering News. 96 (8): 6.
  4. 1 2 3 4 Kaplan S (February 13, 2018). "A potentially powerful new antibiotic is discovered in dirt". The Washington Post . Retrieved February 13, 2018.
  5. 1 2 3 Healy M (13 February 2018). "In soil-dwelling bacteria, scientists find a new weapon to fight drug-resistant superbugs". Los Angeles Times . Retrieved 13 February 2018.
  6. ↑ King A (14 February 2018). "Soil search unearths new class of antibiotics". Chemistry World.
  7. 1 2 3 "New antibiotic family discovered in dirt". BBC . 13 February 2018. Retrieved 13 February 2018.
  8. 1 2 Hotz RL (12 February 2018). "Scientists Unearth Hope for New Antibiotics". Wall Street Journal. Retrieved 2018-02-18.
  9. ↑ Jarvis LM (October 31, 2016). "Lodo Therapeutics". Chemical & Engineering News.
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