Eleftheria terrae

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Eleftheria terrae
Scientific classification
Domain:
Bacteria
Phylum:
Pseudomonadota
Class:
Betaproteobacteria
Genus:
Eleftheria
Species:
E. terrae
Binomial name
Eleftheria terrae
Ling et al., 2015

Eleftheria terrae is a recently discovered Gram-negative bacterium. [1] E. terrae is a temporary name for the organism, as it was only discovered in 2014 and is still undergoing scientific study. It was found to produce a previously unknown antibiotic named teixobactin. The discovery of E. terrae could represent a new age of antibiotics, as teixobactin is the first new antibiotic discovered since the synthetic era of the 1980s. [2] Prior research has indicated that other uncultivable bacteria like E. terrae have potential in the development of new antimicrobial agents. [1]

Contents

Discovery

As of 2015, an estimated 99% of bacterial species are uncultured and require advanced means, such as the iChip, to be isolated. [3] E. terrae is one such bacterium affectionately named by scientists "microbial dark matter" cultivated by emerging scientific methods. [1] A team from Novobiotic Pharmaceuticals led by L. Ling discovered Eleftheria terrae in the fall of 2014 in a field in Maine using a technique developed at Northeastern University called the iChip or isolation chip technique. [4] The iChip is a small plastic block that contains 192 holes going through it. [3] The holes are filled with a culture medium that are then inoculated with soil diluted to deposit only one bacterium in each hole. [3] After depositing the bacterium in the holes the iChip is covered on both sides by a semipermeable membrane and put into a box of the original soil. [3] The permeable membranes allow nutrients and growth factors from the soil to diffuse in and allow growth of only one species. [3] Ling et al. screened approximately 10,000 iChip growth isolates for prospective antimicrobial activity, and E. terrae seemed to be hopeful. [1] This technology has potential for discovering even more antibiotics by allowing labs to grow previously "unculturable" microorganisms. [5]

General characteristics

E. terrae is a Gram-negative bacterium which produces several novel antibiotics including teixobactin and clovibactin. E. terrae grows and produces antibacterial activity under many different growth conditions, but optimally in R4 fermentation broth. R4 fermentation broth consists of 10g glucose, 1g yeast extract, 0.1g casamino acids, 3g proline, 10g MgCl2·6H2O, 4g CaCl2·2H2O, 0.2g K2SO4, 5.6g TES free acid per liter of deionized H2O at pH 7. [1] E. terrae's metabolism and ecology have not yet been extensively documented.

Phylogeny

E. terrae belongs to the class beta-proteobacteria. [1] After sequencing the organism's genome it was concluded that E. terrae is a member of a previously unknown genus close in genetic makeup to Aquabacteria based upon its 16S rRNA gene sequencing and DNA-DNA hybridization performed by computer analysis. [1] Organisms of the genus Aquabacteria had not been known to produce antibiotics until E. terrae´s discovery. [1]

Genomics

Ling and her team sequenced the genome of E. terrae and estimated it to be 6.6 Mbp in length, using an in house pipeline by TUCF Genomics. [1] After the draft genome was assembled it was screened for sequences closely related to adenylation domains. [1] Contigs that were found to code for teixobactin biosynthetic pathways were manually edited and placed in order. [1] This allowed the combination of other contigs that were separately assembled. [1] Any gaps that remained in the genome were filled using bridging fragments developed by PCR and Sanger sequencing. [1] The gaps were closed using the same primers used in amplification. [1]

Antibiotic production

E. terrae's production of teixobactin is prominent because recent tests have revealed that teixobactin binds differently than most normally used antibiotics which makes it harder for the bacteria being attacked to develop resistance. [1] Experiments performed by Ling et al. have shown teixobactin is capable of binding to lipid precursors of peptidoglycan, which makes up part of bacterial cell walls. [1] The results did not show any resistance to teixobactin in the organisms that were studied, including Staphylococcus aureus and Mycobacterium tuberculosis . [1] These findings indicate that teixobactin's target is not a protein, leading to the belief that the development of bacterial resistance to teixobactin is much less likely. [1] These experiments also showed that teixobactin followed a similar mechanism of action as the antibiotic vancomycin that binds to the lipid II molecule in peptidoglycan precursors but, unlike vancomycin, teixobactin is capable of binding to modified lipid II molecules found in vancomycin resistant bacteria. [1] Teixobactin's inhibition of peptidoglycan synthesis is further explained by Ling's finding of a buildup of undecaprenyl-N-acetylmuramic acid-pentapeptide, a crucial step in the biosynthesis of peptidoglycan. [1] According to Ling's tests, teixobactin is capable of inhibiting peptidoglycan synthesis by binding to either lipid I, lipid II, and undecaprenyl pyrophosphate. [1] Teixobactin also seemed to be specifically involved with peptidoglycan precursors rather than blocking enzyme activity. [1]

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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.

<span class="mw-page-title-main">Beta-lactam antibiotics</span> Class of broad-spectrum antibiotics

β-lactam antibiotics are antibiotics that contain a beta-lactam ring in their chemical structure. This includes penicillin derivatives (penams), cephalosporins and cephamycins (cephems), monobactams, carbapenems and carbacephems. Most β-lactam antibiotics work by inhibiting cell wall biosynthesis in the bacterial organism and are the most widely used group of antibiotics. Until 2003, when measured by sales, more than half of all commercially available antibiotics in use were β-lactam compounds. The first β-lactam antibiotic discovered, penicillin, was isolated from a strain of Penicillium rubens.

<span class="mw-page-title-main">Vancomycin</span> Pharmaceutical drug

Vancomycin is a glycopeptide antibiotic medication used to treat a number of bacterial infections. It is used intravenously as a treatment for complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, and meningitis caused by methicillin-resistant Staphylococcus aureus. Blood levels may be measured to determine the correct dose. Vancomycin is also taken orally as a treatment for severe Clostridium difficile colitis. When taken orally it is poorly absorbed.

<span class="mw-page-title-main">Drug resistance</span> Pathogen resistance to medications

Drug resistance is the reduction in effectiveness of a medication such as an antimicrobial or an antineoplastic in treating a disease or condition. The term is used in the context of resistance that pathogens or cancers have "acquired", that is, resistance has evolved. Antimicrobial resistance and antineoplastic resistance challenge clinical care and drive research. When an organism is resistant to more than one drug, it is said to be multidrug-resistant.

The cell envelope comprises the inner cell membrane and the cell wall of a bacterium. In gram-negative bacteria an outer membrane is also included. This envelope is not present in the Mollicutes where the cell wall is absent.

<span class="mw-page-title-main">Glycopeptide antibiotic</span> Class of antibiotic drugs

Glycopeptide antibiotics are a class of drugs of microbial origin that are composed of glycosylated cyclic or polycyclic nonribosomal peptides. Significant glycopeptide antibiotics include the anti-infective antibiotics vancomycin, teicoplanin, telavancin, ramoplanin and decaplanin, corbomycin, complestatin and the antitumor antibiotic bleomycin. Vancomycin is used if infection with methicillin-resistant Staphylococcus aureus (MRSA) is suspected.

<span class="mw-page-title-main">Antibiotic sensitivity testing</span> Microbiology test used in medicine

Antibiotic sensitivity testing or antibiotic susceptibility testing is the measurement of the susceptibility of bacteria to antibiotics. It is used because bacteria may have resistance to some antibiotics. Sensitivity testing results can allow a clinician to change the choice of antibiotics from empiric therapy, which is when an antibiotic is selected based on clinical suspicion about the site of an infection and common causative bacteria, to directed therapy, in which the choice of antibiotic is based on knowledge of the organism and its sensitivities.

<span class="mw-page-title-main">Penicillin-binding proteins</span> Class of proteins

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<span class="mw-page-title-main">Dalbavancin</span> Antibiotic used to treat MRSA

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NovoBiotic Pharmaceuticals is a privately held, early-stage biotechnology company focused on the discovery and development of new drugs from natural sources.

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

Lipid II is a precursor molecule in the synthesis of the cell wall of bacteria. It is a peptidoglycan, which is amphipathic and named for its bactoprenol hydrocarbon chain, which acts as a lipid anchor, embedding itself in the bacterial cell membrane. Lipid II must translocate across the cell membrane to deliver and incorporate its disaccharide-pentapeptide "building block" into the peptidoglycan mesh. Lipid II is the target of several antibiotics.

Mycoplasma orale is a small bacterium found in the class Mollicutes. It belongs to the genus Mycoplasma, a well-known group of bacterial parasites that inhabit humans. It also is known to be an opportunistic pathogen in immunocompromised humans. As with other Mycoplasma species, M. orale is not readily treated with many antibiotics due to its lack of a peptidoglycan cell wall. Therefore, this species is relevant to the medical field as physicians face the task of treating patients infected with this microbe. It is characterized by a small physical size, a small genome size, and a limited metabolism. It is also known to frequently contaminate laboratory experiments. This bacteria is very similar physiologically and morphologically to its sister species within the genus Mycoplasma; however, its recent discovery leaves many questions still unanswered about this microbe.

The Isolation chip is a method of culturing bacteria. Using regular methods, 99% of bacterial species are not able to be cultured as they do not grow in conditions made in a laboratory, a problem called the "Great Plate Count Anomaly". The ichip instead cultures bacterial species within its soil environment. The soil is diluted in molten agar and nutrients such that only a single cell, on average, grows in the ichip's small compartments or wells, hence the term "isolation". The chip is then enclosed in a semipermeable plastic membrane and buried back in the dirt to allow in nutrients not available in the lab. With this culturing method, about 50 to 60 percent of bacterial species are able to survive. Notably, the bacterial species Eleftheria terrae, which makes the antibiotic teixobactin that has shown promise against many drug-resistant strains like methicillin-resistant Staphylococcus aureus, was discovered using the ichip in 2015. In addition to antibiotics, it is argued that anti-cancer agents, anti-inflammatory and immunosuppressives as well as potential energy sources could be discovered. The ichip was developed by the drug discovery company NovoBiotic Pharmaceuticals, founded by Kim Lewis and Slava Epstein.

In microbiology, the term isolation refers to the separation of a strain from a natural, mixed population of living microbes, as present in the environment, for example in water or soil, or from living beings with skin flora, oral flora or gut flora, in order to identify the microbe(s) of interest. Historically, the laboratory techniques of isolation first developed in the field of bacteriology and parasitology, before those in virology during the 20th century.

Kim Lewis is an American researcher, author and academic. He is a University Distinguished Professor and the director of Antimicrobial Discovery Center at Northeastern University.

Slava Epstein is an American academic, researcher and entrepreneur working in the field of Microbial ecology. He is currently a professor in the biology department of Northeastern University and co-founder of NovoBiotic Pharmaceuticals. As a researcher his most covered contribution is the development of the Isolation chip (iChip) and the discovery of a new antibiotic, Teixobactin. Epstein's research has been published in many leading scientific journals including Nature and Science.

Undecaprenyl phosphate (UP), also known lipid-P, bactoprenol and C55-P., is a molecule with the primary function of trafficking polysaccharides across the cell membrane, largely contributing to the overall structure of the cell wall in Gram-positive bacteria. In some situations, UP can also be utilized to carry other cell-wall polysaccharides, but UP is the designated lipid carrier for peptidoglycan. During the process of carrying the peptidoglycan across the cell membrane, N-acetylglucosamine and N-acetylmuramic acid are linked to UP on the cytoplasmic side of the membrane before being carried across. UP works in a cycle of phosphorylation and dephosphorylation as the lipid carrier gets used, recycled, and reacts with undecaprenyl phosphate. This type of synthesis is referred to as de novo synthesis where a complex molecule is created from simpler molecules as opposed to a complete recycle of the entire structure.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Ling LL, Schneider T, Peoples AJ, Spoering AL, Engels I, Conlon BP, Mueller A, Schäberle TF, Hughes DE, Epstein S, Jones M, Lazarides L, Steadman VA, Cohen DR, Felix CR, Fetterman KA, Millett WP, Nitti AG, Zullo AM, Chen C, Lewis K (7 January 2015). "A new antibiotic kills pathogens without detectable resistance". Nature . 517 (7535): 455–459. Bibcode:2015Natur.517..455L. doi:10.1038/nature14098. PMC   7414797 . PMID   25561178.
  2. ↑ Wright, Gerard (7 January 2015). "Antibiotics: An irresistible newcomer". Nature. 517 (7535): 442–444. Bibcode:2015Natur.517..442W. doi: 10.1038/nature14193 . PMID   25561172. S2CID   4464402.
  3. 1 2 3 4 5 Nichols, D.; Cahoon, N.; Trakhtenberg, E. M.; Pham, L.; Mehta, A.; Belanger, A.; Kanigan, T.; Lewis, K.; Epstein, S. S. (19 February 2010). "Use of Ichip for High-Throughput In Situ Cultivation of "Uncultivable" Microbial Species". Applied and Environmental Microbiology. 76 (8): 2445–2450. Bibcode:2010ApEnM..76.2445N. doi:10.1128/AEM.01754-09. PMC   2849220 . PMID   20173072.
  4. ↑ Servick, Kelly (7 January 2015). "Microbe found in grassy field contains powerful antibiotic". Science. doi:10.1126/science.aaa6305.
  5. ↑ Ledford, Heidi (7 January 2015). "Promising antibiotic discovered in microbial 'dark matter'". Nature. doi:10.1038/nature.2015.16675. S2CID   87719690.
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