Lactocillin

Last updated
Lactocillin
Lactocillin.svg
Names
IUPAC name
N-({2'-[(26Z)-26-Ethyliden-19,29-bis(1-hydroxyethyl)-12-{[(1H-indol-3-ylcarbonyl)sulfanyl]methyl}-14,21,28,31-tetraoxo-10,17,24,34-tetrathia-6,13,20,27,30,35,36,37,38-nonaazahexacyclo[30.2.1.18,11.115,18.122,25.02,7]octatriaconta-1(35),2,4,6,8,11(38),18(37),22,25(36),32-decaen-5-yl]-2,4'-bi-1,3-thiazol-4-yl}carbonyl)alanine
Identifiers
3D model (JSmol)
ChemSpider
PubChem CID
  • InChI=1S/C51H45N13O10S7/c1-5-26-45-59-33(16-77-45)42(70)64-37(22(4)66)49-61-31(17-80-49)40(68)56-34(19-81-51(74)25-12-52-27-9-7-6-8-23(25)27)47-57-29(13-76-47)38-24(44-58-32(14-75-44)41(69)63-36(21(3)65)43(71)55-26)10-11-28(54-38)46-62-35(18-79-46)48-60-30(15-78-48)39(67)53-20(2)50(72)73/h5-16,18,20-22,31,34,36-37,52,65-66H,17,19H2,1-4H3,(H,53,67)(H,55,71)(H,56,68)(H,63,69)(H,64,70)(H,72,73)/b26-5-
    Key: WTPCCOAKKCTBIB-PLYROHNOSA-N
  • C/C=C\1/c2nc(cs2)C(=O)NC(C3=NC(CS3)C(=O)NC(c4nc(cs4)-c5c(ccc(n5)c6nc(cs6)c7nc(cs7)C(=O)NC(C)C(=O)O)-c8nc(cs8)C(=O)NC(C(=O)N1)C(C)O)CSC(=O)c9c[nH]c1c9cccc1)C(C)O
Properties
C51H45N13O10S7
Molar mass 1224.42 g·mol−1
Density 1.8 g/cm3
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

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. [1] Lactobacillus gasseri is one of the four Lactobacillus bacteria found to be most common in the human vaginal microbiome. [2] 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.

Contents

Biosynthetic Gene Clusters

Lactocillin is produced by a biosynthetic gene cluster, which is a group of genes in bacteria that work together to make a secondary metabolite. [3] Secondary metabolites are molecules with many different chemical structures and functions, and in this case, lactocillin functions as an antibiotic. [3]

Biosynthetic gene clusters are similar to operons in bacteria in that they both code for proteins that function together in a common process. However, biosynthetic gene clusters always code for a known secondary metabolite, while operons are a general group of genes under one promoter. Operons can code for a specific molecule, similar to BGC’s, or other things such as associated proteins that work together in a common function, such as lac operon coding for the proteins involved in breaking down lactose.[ citation needed ]

Lactocillin is made by biosynthetic gene cluster 66 (bgc66) which is located on a plasmid in Lactobacillus gasseri. [1] bgc66 has many different genes that code for the proteins shown in the table below and perform the indicated function involved in the synthesis of lactocillin. [1]

Lactocillin BGC Proteins and Functions [1]
ProteinFunction
YcaOAids in heterocycle formation, as we see five cysteine derived heterocycles in lactocillin. [4]
cyclodehydrataseAids in heterocycle formation, as we see five cysteine derived heterocycles in lactocillin. [4]
Lantibiotic DH (2 different genes of this type)Makes dehydrobutyrine residues, as one is seen in lactocillin. [5]
TclMAids in the production of the trithiazoylpyridine core of lactocillin. [1]
Other post-translation modification enzymesHelp continue to adjust the structure of lactocillin after translation.
Regulatory proteinsRegulate transcription of the BGC. [1]

Thiopeptides

Antibiotics are chemicals used to inhibit or kill microbes, and come in many different chemical classes. Thiopeptides are a fairly new chemical class of antibiotics, characterized by a central six-membered ring with a nitrogen in the ring. Certain thiopeptides are created by bacteria found in other unusual places such as marine life and soil, but lactocillin is made by bacteria found in human vaginal and oral microbiomes. [1]

Thiopeptides work well against gram positive bacteria but not gram negative bacteria. [1] Thiopeptides have even been found to be potentially effective in fighting MRSA. [6] Thiopeptides are seen to potentially have many functions such as “anticancer, antiplasmodial, immunosuppressive, renin inhibitory, RNA polymerase inhibitory, and antifungal activities”. [7]

Thiopeptides function as antibiotic by blocking ribosomal protein synthesis. [7] This is an example of post-transcriptional regulation, as the thiopeptides do not affect transcription of the proteins but do prevent translation.[ citation needed ]

Lactocillin is different from thiocillin (a well-studied thiopeptide) in 3 important ways.  Lactocillin 1) has a free carboxylic acid at C-terminus, 2) doesn’t undergo any post-translation modifications that require oxygen, and 3) has an indolyl-S-cysteine residue at position 8. [1] These differences suggest that this thiopeptide may function differently than the others, but more research needs to be done to determine if this is accurate.

Structure

Lactocillin has an empirical formula of C51H45N13O10S7 and has a picture as shown above, as determined using NMR and UV-Vis absorbance profiles. [1] The structure of this protein does not perfectly match up to the sequence of bcg66. This illustrates that there must be some sort of post-translational modification. [1]

Plasmid harboring and Horizontal Gene Transfer

Horizontal gene transfer (HGT) is the mechanism by which bacteria can share genes, besides from parent to offspring in reproduction. Bacteria can add genes to their genome that may improve their fitness by taking in genetic material from other bacteria, the environment, or bacteriophages through HGT.[ citation needed ]

bgc66 is located on a plasmid along with other maintenance, regulatory, transfer, and transposases sequences. [1] The presence of these transfer sequences shows us that this plasmid can participate in HGT leading to other bacteria being able to produce lactocillin. The transposase sequences suggest that the plasmid might have even further capabilities of gene transfer through the cutting out and insertion of certain genes through the use of transposase proteins. If lactocillin is further studied and determined to have desirable properties, the fact that the BGC for lactocillin’s production resides on a transferable plasmid would make it easier for chemical companies to mass produce it.[ citation needed ]

Function in Human Body

Lactocillin is seen to be very functional in killing certain pathogens. [1] The minimum inhibitory concentration (MIC) of an antibiotic is the lowest concentration of an antibiotic needed to inhibit the growth of a bacteria. The MIC was calculated for many different bacteria that commonly infect human vaginas. This approach makes sense, as a non-pathogenic bacterium found in the vaginal microbiota might provide a benefit to the host, such as resistance to potential pathogens that commonly infect that area of the body, because the host’s survival is essential for the bacteria’s survival.[ citation needed ]

Growth was observed at multiple different concentrations to obtain the MIC of lactocillin for different pathogens. Lactocillin was found to be most effective at preventing growth of Staphylococcus aureus, Corynebacterium aurimucosum, and Streptococcus sobrinus , but was also effective at inhibiting growth at higher concentrations for other bacterial pathogens. These well inhibited bacteria cause Staph infections, urinary tract infections, [8] and cavities. [9] This suggests that lactocillin could potentially be used as a common antimicrobial in the future.[ citation needed ]

Lactocillin was not seen to prevent growth of other bacteria that are known to be common and beneficial to the vaginal microbiome. This makes sense, as killing these bacteria would be deleterious to a human’s health and, in consequence, also deleterious to the bacteria’s chance at survival. [10]

Other Lactobacillus bacteria have been seen to also be used as probiotics. [11] Lactobacillus gasseri could potentially function similarly to these other Lactobacillus bacteria and be used as a probiotic, helping with overall health such as immunity, cholesterol levels, and skin health. [11]

Related Research Articles

<i>Lactobacillus</i> Genus of bacteria

Lactobacillus is a genus of gram-positive, aerotolerant anaerobes or microaerophilic, rod-shaped, non-spore-forming bacteria. Until 2020, the genus Lactobacillus comprised over 260 phylogenetically, ecologically, and metabolically diverse species; a taxonomic revision of the genus assigned lactobacilli to 25 genera.

<span class="mw-page-title-main">Human microbiome</span> Microorganisms in or on human skin and biofluids

The human microbiome is the aggregate of all microbiota that reside on or within human tissues and biofluids along with the corresponding anatomical sites in which they reside, including the gastrointestinal tract, skin, mammary glands, seminal fluid, uterus, ovarian follicles, lung, saliva, oral mucosa, conjunctiva, and the biliary tract. Types of human microbiota include bacteria, archaea, fungi, protists, and viruses. Though micro-animals can also live on the human body, they are typically excluded from this definition. In the context of genomics, the term human microbiome is sometimes used to refer to the collective genomes of resident microorganisms; however, the term human metagenome has the same meaning.

<i>Lactobacillus acidophilus</i> Species of bacterium

Lactobacillus acidophilus is a rod-shaped, Gram-positive, homofermentative, anaerobic microbe first isolated from infant feces in the year 1900. The species is commonly found in humans, specifically the gastrointestinal tract and oral cavity as well as some speciality fermented foods such as fermented milk or yogurt, though it is not the most common species for this. The species most readily grows at low pH levels, and has an optimum growth temperature of 37 °C. Certain strains of L. acidophilus show strong probiotic effects, and are commercially used in dairy production. The genome of L. acidophilus has been sequenced.

<i>Lacticaseibacillus casei</i> Species of bacterium

Lacticaseibacillus casei is an organism that belongs to the largest genus in the family Lactobacillaceae, a lactic acid bacteria (LAB), that was previously classified as Lactobacillus casei. This bacteria has been identified as facultatively anaerobic or microaerophilic, acid-tolerant, non-spore-forming bacteria.

<i>Lacticaseibacillus rhamnosus</i> Species of bacterium

Lacticaseibacillus rhamnosus is a bacterium that originally was considered to be a subspecies of L. casei, but genetic research found it to be a separate species in the L. casei clade, which also includes L. paracasei and L. zeae. It is a short Gram-positive homofermentative facultative anaerobic non-spore-forming rod that often appears in chains. Some strains of L. rhamnosus bacteria are being used as probiotics, and are particularly useful in treating infections of the female urogenital tract, most particularly very difficult to treat cases of bacterial vaginosis. The species Lacticaseibacillus rhamnosus and Limosilactobacillus reuteri are commonly found in the healthy female genito-urinary tract and are helpful to regain control of dysbiotic bacterial overgrowth during an active infection. L. rhamnosus sometimes is used in dairy products such as fermented milk and as non-starter-lactic acid bacterium (NSLAB) in long-ripened cheese. While frequently considered a beneficial organism, L. rhamnosus may not be as beneficial to certain subsets of the population; in rare circumstances, especially those primarily involving weakened immune system or infants, it may cause endocarditis. Despite the rare infections caused by L. rhamnosus, the species is included in the list of bacterial species with qualified presumed safety (QPS) status of the European Food Safety Agency.

In biology, a gene cassette is a type of mobile genetic element that contains a gene and a recombination site. Each cassette usually contains a single gene and tends to be very small; on the order of 500–1,000 base pairs. They may exist incorporated into an integron or freely as circular DNA. Gene cassettes can move around within an organism's genome or be transferred to another organism in the environment via horizontal gene transfer. These cassettes often carry antibiotic resistance genes. An example would be the kanMX cassette which confers kanamycin resistance upon bacteria.

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Levilactobacillus brevis is a gram-positive, rod shaped species of lactic acid bacteria which is heterofermentative, creating CO2, lactic acid and acetic acid or ethanol during fermentation. L. brevis is the type species of the genus Levilactobacillus (previously L. brevis group), which comprises 24 species. It can be found in many different environments, such as fermented foods, and as normal microbiota. L. brevis is found in food such as sauerkraut and pickles. It is also one of the most common causes of beer spoilage. Ingestion has been shown to improve human immune function, and it has been patented several times. Normal gut microbiota L. brevis is found in human intestines, vagina, and feces.

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<span class="mw-page-title-main">Vaginal flora</span> Microorganisms present in the vagina

Vaginal flora, vaginal microbiota or vaginal microbiome are the microorganisms that colonize the vagina. They were discovered by the German gynecologist Albert Döderlein in 1892 and are part of the overall human flora. The amount and type of bacteria present have significant implications for an individual's overall health. The primary colonizing bacteria of a healthy individual are of the genus Lactobacillus, such as L. crispatus, and the lactic acid they produce is thought to protect against infection by pathogenic species.

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<span class="mw-page-title-main">Cyclothiazomycin</span> Chemical compound

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<span class="mw-page-title-main">Uterine microbiome</span>

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References

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  2. ↑ Vásquez, Alejandra; Jakobsson, Tell; Ahrné, Siv; Forsum, Urban; Molin, Göran (August 2002). "Vaginal lactobacillus flora of healthy Swedish women". Journal of Clinical Microbiology. 40 (8): 2746–2749. doi:10.1128/jcm.40.8.2746-2749.2002. ISSN   0095-1137. PMC   120688 . PMID   12149323.
  3. 1 2 Chen, Ray; Wong, Hon Lun; Burns, Brendan Paul (2019-02-25). "New Approaches to Detect Biosynthetic Gene Clusters in the Environment". Medicines. 6 (1): 32. doi: 10.3390/medicines6010032 . ISSN   2305-6320. PMC   6473659 . PMID   30823559.
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  5. ↑ Ortega, Manuel A.; Hao, Yue; Zhang, Qi; Walker, Mark C.; van der Donk, Wilfred A.; Nair, Satish K. (2015-01-22). "Structure and Mechanism of the tRNA-Dependent Lantibiotic Dehydratase NisB". Nature. 517 (7535): 509–512. Bibcode:2015Natur.517..509O. doi:10.1038/nature13888. ISSN   0028-0836. PMC   4430201 . PMID   25363770.
  6. ↑ Haste, Nina M.; Thienphrapa, Wdee; Tran, Dan N.; Loesgen, Sandra; Sun, Peng; Nam, Sang-Jip; Jensen, Paul R.; Fenical, William; Sakoulas, George; Nizet, Victor; Hensler, Mary E. (December 2012). "Activity of the thiopeptide antibiotic nosiheptide against contemporary strains of methicillin-resistant Staphylococcus aureus". The Journal of Antibiotics. 65 (12): 593–598. doi:10.1038/ja.2012.77. ISSN   1881-1469. PMC   3528839 . PMID   23047246.
  7. 1 2 Just-Baringo, Xavier; Albericio, Fernando; Álvarez, Mercedes (2014-01-17). "Thiopeptide antibiotics: retrospective and recent advances". Marine Drugs. 12 (1): 317–351. doi: 10.3390/md12010317 . ISSN   1660-3397. PMC   3917276 . PMID   24445304.
  8. ↑ Lo, Seynabou; Thiam, Issa; Fall, Bécaye; Ba-Diallo, Awa; Diallo, Oumarou Foly; Diagne, Rokhaya; Dia, Mamadou Lamine; Ka, Roughyatou; Sarr, Aicha Marceline; Sow, Ahmad Iyane (2015-07-14). "Urinary tract infection with Corynebacterium aurimucosum after urethroplasty stricture of the urethra: a case report". Journal of Medical Case Reports. 9: 156. doi: 10.1186/s13256-015-0638-0 . ISSN   1752-1947. PMC   4501104 . PMID   26155836.
  9. ↑ Conrads, Georg; de Soet, Johannes J.; Song, Lifu; Henne, Karsten; Sztajer, Helena; Wagner-Döbler, Irene; Zeng, An-Ping (2014). "Comparing the cariogenic species Streptococcus sobrinus and S. mutans on whole genome level". Journal of Oral Microbiology. 6: 26189. doi:10.3402/jom.v6.26189. ISSN   2000-2297. PMC   4256546 . PMID   25475081.
  10. ↑ Milshteyn, Aleksandr; Colosimo, Dominic A.; Brady, Sean F. (13 June 2018). "Accessing Bioactive Natural Products from the Human Microbiome". Cell Host & Microbe. 23 (6): 725–736. doi:10.1016/j.chom.2018.05.013. ISSN   1934-6069. PMC   7232905 . PMID   29902438.
  11. 1 2 Reid, Gregor (1999-09-01). "The Scientific Basis for Probiotic Strains ofLactobacillus". Applied and Environmental Microbiology. 65 (9): 3763–3766. Bibcode:1999ApEnM..65.3763R. doi: 10.1128/AEM.65.9.3763-3766.1999 . ISSN   1098-5336. PMC   99697 . PMID   10473372.
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