SPR741

Last updated

SPR741
SPR741.svg
Skeletal formula of SPR741
SPR741 2.svg
peptide depiction (DAB = Diaminobutyric acid)
Clinical data
Other namesNAB741
Legal status
Legal status
  • Investigational
Identifiers
  • (2S,3R)-2-Acetamido-3-hydroxy-N-[(2R)-3-hydroxy-1-oxo-1-[[(3S,6S,9S,12S,15R,18S,21S)-6,9,18-tris(2-aminoethyl)-15-benzyl-3-[(1R)-1-hydroxyethyl]-12-(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]propan-2-yl]butanamide
CAS Number
PubChem CID
IUPHAR/BPS
ChEMBL
Chemical and physical data
Formula C44H73N13O13
Molar mass 992.146 g·mol−1
3D model (JSmol)
  • C[C@H]([C@H]1C(=O)NCC[C@@H](C(=O)N[C@H](C(=O)N[C@@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N1)CCN)CCN)CC(C)C)CC2=CC=CC=C2)CCN)NC(=O)[C@@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)C)O
  • InChI=1S/C44H73N13O13/c1-22(2)19-31-40(66)52-27(11-15-45)36(62)51-29(13-17-47)39(65)57-34(23(3)59)43(69)48-18-14-30(53-42(68)33(21-58)56-44(70)35(24(4)60)49-25(5)61)38(64)50-28(12-16-46)37(63)55-32(41(67)54-31)20-26-9-7-6-8-10-26/h6-10,22-24,27-35,58-60H,11-21,45-47H2,1-5H3,(H,48,69)(H,49,61)(H,50,64)(H,51,62)(H,52,66)(H,53,68)(H,54,67)(H,55,63)(H,56,70)(H,57,65)/t23-,24-,27+,28+,29+,30+,31+,32-,33-,34+,35+/m1/s1
  • Key:JBFNEVNUGGFPBQ-DDMCRLCFSA-N

SPR741 is an experimental antibiotic related to Polymyxin B. It shows activity against a number of bacterial pathogens, especially Acinetobacter baumannii and Klebsiella pneumoniae , acting as an antibiotic adjuvant which disrupts the outer membrane of Gram-negative bacteria and allows other antibiotics to more effectively penetrate into the cell. [1] [2] [3] [4]

Related Research Articles

<span class="mw-page-title-main">Gram-negative bacteria</span> Group of bacteria that do not retain the Gram stain used in bacterial differentiation

Gram-negative bacteria are bacteria that, unlike gram-positive bacteria, do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. Their defining characteristic is their cell envelope, which consists of a thin peptidoglycan cell wall sandwiched between an inner (cytoplasmic) membrane and an outer membrane. These bacteria are found in all environments that support life on Earth.

<i>Klebsiella pneumoniae</i> Species of bacterium

Klebsiella pneumoniae is a Gram-negative, non-motile, encapsulated, lactose-fermenting, facultative anaerobic, rod-shaped bacterium. It appears as a mucoid lactose fermenter on MacConkey agar.

<i>Acinetobacter</i> Genus of bacteria

Acinetobacter is a genus of Gram-negative bacteria belonging to the wider class of Gammaproteobacteria. Acinetobacter species are oxidase-negative, exhibit twitching motility, and occur in pairs under magnification.

<span class="mw-page-title-main">Polymyxin</span> Group of antibiotics

Polymyxins are antibiotics. Polymyxins B and E are used in the treatment of Gram-negative bacterial infections. They work mostly by breaking up the bacterial cell membrane. They are part of a broader class of molecules called nonribosomal peptides.

<span class="mw-page-title-main">Colistin</span> Antibiotic

Colistin, also known as polymyxin E, is an antibiotic medication used as a last-resort treatment for multidrug-resistant Gram-negative infections including pneumonia. These may involve bacteria such as Pseudomonas aeruginosa, Klebsiella pneumoniae, or Acinetobacter. It comes in two forms: colistimethate sodium can be injected into a vein, injected into a muscle, or inhaled, and colistin sulfate is mainly applied to the skin or taken by mouth. Colistimethate sodium is a prodrug; it is produced by the reaction of colistin with formaldehyde and sodium bisulfite, which leads to the addition of a sulfomethyl group to the primary amines of colistin. Colistimethate sodium is less toxic than colistin when administered parenterally. In aqueous solutions it undergoes hydrolysis to form a complex mixture of partially sulfomethylated derivatives, as well as colistin. Resistance to colistin began to appear as of 2015.

<span class="mw-page-title-main">Bacterial pneumonia</span> Disease of the lungs

Bacterial pneumonia is a type of pneumonia caused by bacterial infection.

<span class="mw-page-title-main">Bacterial capsule</span> Polysaccharide layer that lies outside the cell envelope in many bacteria

The bacterial capsule is a large structure common to many bacteria. It is a polysaccharide layer that lies outside the cell envelope, and is thus deemed part of the outer envelope of a bacterial cell. It is a well-organized layer, not easily washed off, and it can be the cause of various diseases.

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.

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

Tigecycline, sold under the brand name Tygacil, is a tetracycline antibiotic medication for a number of bacterial infections. It is a glycylcycline class drug that is administered intravenously. It was developed in response to the growing rate of antibiotic resistant bacteria such as Staphylococcus aureus, Acinetobacter baumannii, and E. coli. As a tetracycline derivative antibiotic, its structural modifications has expanded its therapeutic activity to include Gram-positive and Gram-negative organisms, including those of multi-drug resistance.

<span class="mw-page-title-main">Carbapenem</span> Class of highly effective antibiotic agents

Carbapenems are a class of very effective antibiotic agents most commonly used for treatment of severe bacterial infections. This class of antibiotics is usually reserved for known or suspected multidrug-resistant (MDR) bacterial infections. Similar to penicillins and cephalosporins, carbapenems are members of the beta-lactam antibiotics drug class, which kill bacteria by binding to penicillin-binding proteins, thus inhibiting bacterial cell wall synthesis. However, these agents individually exhibit a broader spectrum of activity compared to most cephalosporins and penicillins. Furthermore, carbapenems are typically unaffected by emerging antibiotic resistance, even to other beta-lactams.

<i>Acinetobacter baumannii</i> Species of bacterium

Acinetobacter baumannii is a typically short, almost round, rod-shaped (coccobacillus) Gram-negative bacterium. It is named after the bacteriologist Paul Baumann. It can be an opportunistic pathogen in humans, affecting people with compromised immune systems, and is becoming increasingly important as a hospital-derived (nosocomial) infection. While other species of the genus Acinetobacter are often found in soil samples, it is almost exclusively isolated from hospital environments. Although occasionally it has been found in environmental soil and water samples, its natural habitat is still not known.

<span class="mw-page-title-main">New Delhi metallo-beta-lactamase 1</span> Enzyme

NDM-1 is an enzyme that makes bacteria resistant to a broad range of beta-lactam antibiotics. These include the antibiotics of the carbapenem family, which are a mainstay for the treatment of antibiotic-resistant bacterial infections. The gene for NDM-1 is one member of a large gene family that encodes beta-lactamase enzymes called carbapenemases. Bacteria that produce carbapenemases are often referred to in the news media as "superbugs" because infections caused by them are difficult to treat. Such bacteria are usually sensitive only to polymyxins and tigecycline.

Multidrug resistant Gram-negative bacteria are a type of Gram-negative bacteria with resistance to multiple antibiotics. They can cause bacteria infections that pose a serious and rapidly emerging threat for hospitalized patients and especially patients in intensive care units. Infections caused by MDR strains are correlated with increased morbidity, mortality, and prolonged hospitalization. Thus, not only do these bacteria pose a threat to global public health, but also create a significant burden to healthcare systems.

<i>Autographiviridae</i> Subfamily of viruses

Autographiviridae is a family of viruses in the order Caudovirales. Bacteria serve as natural hosts. There are 373 species in this family, assigned to 9 subfamilies and 133 genera.

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

Eravacycline is a synthetic halogenated tetracycline class antibiotic by Tetraphase Pharmaceuticals. It is closely related to tigecycline. It has a broad spectrum of activity including many multi-drug resistant strains of bacteria. Phase III studies in complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI) were recently completed with mixed results. Eravacycline was granted fast track designation by the FDA and is currently available in USA.

<span class="mw-page-title-main">MCR-1</span>

The mobilized colistin resistance (mcr) gene confers plasmid-mediated resistance to colistin, one of a number of last-resort antibiotics for treating Gram-negative infections. mcr-1, the original variant, is capable of horizontal transfer between different strains of a bacterial species. After discovery in November 2015 in E. coli from a pig in China it has been found in Escherichia coli, Salmonella enterica, Klebsiella pneumoniae, Enterobacter aerogenes, and Enterobacter cloacae. As of 2017, it has been detected in more than 30 countries on 5 continents in less than a year.

ESKAPE is an acronym comprising the scientific names of six highly virulent and antibiotic resistant bacterial pathogens including: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp. The acronym is sometimes extended to ESKAPEE to include Escherichia coli. This group of Gram-positive and Gram-negative bacteria can evade or 'escape' commonly used antibiotics due to their increasing multi-drug resistance (MDR). As a result, throughout the world, they are the major cause of life-threatening nosocomial or hospital-acquired infections in immunocompromised and critically ill patients who are most at risk. P. aeruginosa and S. aureus are some of the most ubiquitous pathogens in biofilms found in healthcare. P. aeruginosa is a Gram-negative, rod-shaped bacterium, commonly found in the gut flora, soil, and water that can be spread directly or indirectly to patients in healthcare settings. The pathogen can also be spread in other locations through contamination, including surfaces, equipment, and hands. The opportunistic pathogen can cause hospitalized patients to have infections in the lungs, blood, urinary tract, and in other body regions after surgery. S. aureus is a Gram-positive, cocci-shaped bacterium, residing in the environment and on the skin and nose of many healthy individuals. The bacterium can cause skin and bone infections, pneumonia, and other types of potentially serious infections if it enters the body. S. aureus has also gained resistance to many antibiotic treatments, making healing difficult. Because of natural and unnatural selective pressures and factors, antibiotic resistance in bacteria usually emerges through genetic mutation or acquires antibiotic-resistant genes (ARGs) through horizontal gene transfer - a genetic exchange process by which antibiotic resistance can spread.

<span class="mw-page-title-main">Cefiderocol</span> Antibiotic

Cefiderocol, sold under the brand name Fetroja among others, is an antibiotic used to treat complicated urinary tract infections when no other options are available. It is indicated for the treatment of multi-drug-resistant Gram-negative bacteria including Pseudomonas aeruginosa. It is given by injection into a vein.

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

Fluorothiazinone is an antibiotic drug, first developed in Russia in 2010 and active against various species of Gram-negative bacteria through inhibition of the type III secretion system (T3SS). It has seen limited clinical use in Russia and is in clinical trials which may eventually see it accepted for use more widely.

References

  1. Eckburg PB, Lister T, Walpole S, Keutzer T, Utley L, Tomayko J, et al. (September 2019). "Safety, Tolerability, Pharmacokinetics, and Drug Interaction Potential of SPR741, an Intravenous Potentiator, after Single and Multiple Ascending Doses and When Combined with β-Lactam Antibiotics in Healthy Subjects". Antimicrobial Agents and Chemotherapy. 63 (9). doi:10.1128/AAC.00892-19. PMC   6709486 . PMID   31262767.
  2. Vaara M (January 2019). "Polymyxin Derivatives that Sensitize Gram-Negative Bacteria to Other Antibiotics". Molecules. 24 (2): 249. doi: 10.3390/molecules24020249 . PMC   6359160 . PMID   30641878.
  3. She P, Liu Y, Xu L, Li Y, Li Z, Liu S, et al. (2022). "SPR741, Double- or Triple-Combined With Erythromycin and Clarithromycin, Combats Drug-Resistant Klebsiella pneumoniae, Its Biofilms, and Persister Cells". Frontiers in Cellular and Infection Microbiology. 12: 858606. doi: 10.3389/fcimb.2022.858606 . PMC   8971605 . PMID   35372124.
  4. Li Z, She P, Liu Y, Xu L, Li Y, Liu S, et al. (January 2023). "Triple combination of SPR741, clarithromycin, and erythromycin against Acinetobacter baumannii and its tolerant phenotype". Journal of Applied Microbiology. 134 (1). doi:10.1093/jambio/lxac023. PMID   36626755.