Lysostaphin

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Lysostaphin
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EC no. 3.4.24.75
CAS no. 9011-93-2
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Lysostaphin (EC 3.4.24.75, glycyl-glycine endopeptidase) is a Staphylococcus simulans metalloendopeptidase (crystal structure of lysostaphin). It can function as a bacteriocin (antimicrobial) against Staphylococcus aureus . [1]

Lysostaphin is a 27 KDa glycylglycine endopeptidase, an antibacterial enzyme which is capable of cleaving the crosslinking pentaglycine bridges found in the cell wall peptidoglycan of certain staphylococci. Lysostaphin was first isolated from a culture of Staphylococcus simulans by Schindler and Schuhardt in 1964. [2] S. aureus cell walls contain high proportions of pentaglycine, making lysostaphin a highly effective agent against both actively growing and quiescent bacteria. [3]

Staphylococcal infections of both Staphylococcus aureus and Staphylococcus epidermidis continue to be a major issue in clinical settings, particularly those with implantable devices. Staphylococci cause a significant percentage of device infections, and like many other pathogens, rather than living as free planktonic cells within the host they have the ability to form a multilayered community of sessile bacteria cells known as a biofilm on implantable devices. Once a staphylococcal biofilm has formed on an implanted medical device, it is difficult to disrupt due to its antibiotic resistance and protection against bacterial action.

Many studies have been previously published on lysostaphin since its isolation, both in vitro and in vivo. Lysostaphin has been shown to eradicate susceptible S. aureus biofilms. It has also been reported to be effective in disrupting S. epidermidis biofilms in vitro, albeit at higher concentrations of the enzyme. [3] Compared to commonly used antibiotics such as vancomycin, lysostaphin has been shown to demonstrate greater antibacterial activity in vitro. [4] The enzyme has demonstrated effectiveness against methicillin susceptible S. aureus (MSSA) and methicillin resistant S. aureus (MRSA) mediated keratitis in vivo in a rabbit model. [5] Additionally, it has been shown that lysostaphin combined with antimicrobials such as cefazolin, clarithromycin, doxycycline, levofloxacin, linezolid and quinuprisitin/dalfopristin has a synergistic effect for MSSA strains of the bacteria. [6] A study published by Belyansky et al. illustrated that a lysostaphin bound mesh demonstrated dramatic preservation results in a rat model. [7]

Using lyostaphin to treat staphylococcal biofilm associated infections may prove to be preferable to using antibiotics as it may be possible to administer the enzyme at relatively low doses and disrupt a staphylococcal bioflim, therefore eliminating the need for surgical removal of the infected device. [3]

Related Research Articles

<i>Staphylococcus aureus</i> Species of Gram-positive bacterium

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 for catalase and nitrate reduction and is a facultative anaerobe that can grow without the need for oxygen. Although S. aureus usually acts as a commensal of the human microbiota, it can also become an opportunistic pathogen, being a common cause of skin infections including abscesses, respiratory infections such as sinusitis, and food poisoning. Pathogenic strains often promote infections by producing virulence factors such as potent protein toxins, and the expression of a cell-surface protein that binds and inactivates antibodies. S. aureus is one of the leading pathogens for deaths associated with antimicrobial resistance and the emergence of antibiotic-resistant strains, such as methicillin-resistant S. aureus (MRSA), is a worldwide problem in clinical medicine. Despite much research and development, no vaccine for S. aureus has been approved.

Methicillin-resistant <i>Staphylococcus aureus</i> Bacterium responsible for difficult-to-treat infections in humans

Methicillin-resistant Staphylococcus aureus (MRSA) is a group of gram-positive bacteria that are genetically distinct from other strains of Staphylococcus aureus. MRSA is responsible for several difficult-to-treat infections in humans. It caused more than 100,000 deaths worldwide attributable to antimicrobial resistance in 2019.

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

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

<i>Staphylococcus haemolyticus</i> Species of bacterium

Staphylococcus haemolyticus is a member of the coagulase-negative staphylococci (CoNS). It is part of the skin flora of humans, and its largest populations are usually found at the axillae, perineum, and inguinal areas. S. haemolyticus also colonizes primates and domestic animals. It is a well-known opportunistic pathogen, and is the second-most frequently isolated CoNS. Infections can be localized or systemic, and are often associated with the insertion of medical devices. The highly antibiotic-resistant phenotype and ability to form biofilms make S. haemolyticus a difficult pathogen to treat. Its most closely related species is Staphylococcus borealis.

<i>Staphylococcus saprophyticus</i> Species of bacterium

Staphylococcus saprophyticus is a Gram-positive coccus belonging to the genus Staphylococcus. S. saprophyticus is a common cause of community-acquired urinary tract infections.

<i>Staphylococcus epidermidis</i> Species of bacterium

Staphylococcus epidermidis is a Gram-positive bacterium, and one of over 40 species belonging to the genus Staphylococcus. It is part of the normal human microbiota, typically the skin microbiota, and less commonly the mucosal microbiota and also found in marine sponges. It is a facultative anaerobic bacteria. Although S. epidermidis is not usually pathogenic, patients with compromised immune systems are at risk of developing infection. These infections are generally hospital-acquired. S. epidermidis is a particular concern for people with catheters or other surgical implants because it is known to form biofilms that grow on these devices. Being part of the normal skin microbiota, S. epidermidis is a frequent contaminant of specimens sent to the diagnostic laboratory.

<span class="mw-page-title-main">Pristinamycin</span> Group of chemical compounds

Pristinamycin (INN), also spelled pristinamycine, is an antibiotic used primarily in the treatment of staphylococcal infections, and to a lesser extent streptococcal infections. It is a streptogramin group antibiotic, similar to virginiamycin, derived from the bacterium Streptomyces pristinaespiralis. It is marketed in Europe by Sanofi-Aventis under the trade name Pyostacine.

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

Dicloxacillin is a narrow-spectrum β-lactam antibiotic of the penicillin class. It is used to treat infections caused by susceptible (non-resistant) Gram-positive bacteria. It is active against beta-lactamase-producing organisms such as Staphylococcus aureus, which would otherwise be resistant to most penicillins. Dicloxacillin is available under a variety of trade names including Diclocil (BMS).

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

Oritavancin, sold under the brand name Orbactiv among others, is a semisynthetic glycopeptide antibiotic medication for the treatment of serious Gram-positive bacterial infections. Its chemical structure as a lipoglycopeptide is similar to vancomycin.

Phenol-soluble modulins (PSMs) are a family of small proteins, that carry out a variety of functions, including acting as toxins, assisting in biofilm formation, and colony spreading. PSMs are produced by Staphylococcus bacteria including Methicillin-resistant Staphylococcus aureus (MRSA), and Staphylococcus epidermidis. Many PSMs are encoded within the core genome and can play an important virulence factor. PSMs were first discovered in S. epidermidis by Seymour Klebanoff and via hot-phenol extraction and were described as a pro-inflammatory complex of three peptides. Since their initial discovery, numerous roles of PSMs have been identified. However, due in part to the small size of many PSMs, they have largely gone unnoticed until recent years.

<span class="mw-page-title-main">Staphylococcal infection</span> Medical condition

A staphylococcal infection or staph infection is an infection caused by members of the Staphylococcus genus of bacteria.

mecA is a gene found in bacterial cells which allows them to be resistant to antibiotics such as methicillin, penicillin and other penicillin-like antibiotics.

<i>Staphylococcus capitis</i> Species of bacterium

Staphylococcus capitis is a coagulase-negative species (CoNS) of Staphylococcus. It is part of the normal flora of the skin of the human scalp, face, neck, scrotum, and ears and has been associated with prosthetic valve endocarditis, but is rarely associated with native valve infection.

<i>Staphylococcus</i> Genus of Gram-positive bacteria

Staphylococcus is a genus of Gram-positive bacteria in the family Staphylococcaceae from the order Bacillales. Under the microscope, they appear spherical (cocci), and form in grape-like clusters. Staphylococcus species are facultative anaerobic organisms.

Biofilm formation occurs when free floating microorganisms attach themselves to a surface. Although there are some beneficial uses of biofilms, they are generally considered undesirable, and means of biofilm prevention have been developed. Biofilms secrete extracellular polymeric substance that provides a structural matrix and facilitates adhesion for the microorganisms; the means of prevention have thus concentrated largely on two areas: killing the microbes that form the film, or preventing the adhesion of the microbes to a surface. Because biofilms protect the bacteria, they are often more resistant to traditional antimicrobial treatments, making them a serious health risk. For example, there are more than one million cases of catheter-associated urinary tract infections (CAUTI) reported each year, many of which can be attributed to bacterial biofilms. There is much research into the prevention of biofilms.

SCCmec, or staphylococcal cassette chromosome mec, is a mobile genetic element of Staphylococcus bacterial species. This genetic sequence includes the mecA gene coding for resistance to the antibiotic methicillin and is the only known way for Staphylococcus strains to spread the gene in the wild by horizontal gene transfer. SCCmec is a 21 to 60 kb long genetic element that confers broad-spectrum β-lactam resistance to MRSA. Moreover, additional genetic elements like Tn554, pT181, and pUB110 can be found in SCCmec, which have the capability to render resistance to various non-β-lactam drugs.

Staphylococcus schleiferi is a Gram-positive, cocci-shaped bacterium of the family Staphylococcaceae. It is facultatively anaerobic, coagulase-variable, and can be readily cultured on blood agar where the bacterium tends to form opaque, non-pigmented colonies and beta (β) hemolysis. There exists two subspecies under the species S. schleiferi: Staphylococcus schleiferi subsp. schleiferi and Staphylococcus schleiferi subsp. coagulans.

Staphylococcus pseudintermedius is a gram positive coccus bacteria of the genus Staphylococcus found worldwide. It is primarily a pathogen for domestic animals, but has been known to affect humans as well. S. pseudintermedius is an opportunistic pathogen that secretes immune modulating virulence factors, has many adhesion factors, and the potential to create biofilms, all of which help to determine the pathogenicity of the bacterium. Diagnoses of Staphylococcus pseudintermedius have traditionally been made using cytology, plating, and biochemical tests. More recently, molecular technologies like MALDI-TOF, DNA hybridization and PCR have become preferred over biochemical tests for their more rapid and accurate identifications. This includes the identification and diagnosis of antibiotic resistant strains.

The arginine catabolic mobile element (ACME) is a mobile genetic element of Staphylococcus bacterial species. This genetic element provides for several immune modulating functions, including resistance to polyamines which serve as a non-specific immune response both on intact skin and following the inflammatory response in wound healing. Diverse ACME are present in several species of Staphylococcus, including Staphylococcus epidermidis.

Kerry L. LaPlante is an American pharmacist, academic and researcher. She is the Dean at the University of Rhode Island College of Pharmacy. She is a Professor of Pharmacy and former department Chair of the Department of Pharmacy Practice at the University of Rhode Island, an Adjunct Professor of Medicine at Brown University, an Infectious Diseases Pharmacotherapy Specialist, and the Director of the Rhode Island Infectious Diseases Fellowship and Research Programs at the Veterans Affairs Medical Center in Providence, Rhode Island.

References

  1. Kokai-Kun JF, Walsh SM, Chanturiya T, Mond JJ (May 2003). "Lysostaphin cream eradicates Staphylococcus aureus nasal colonization in a cotton rat model". Antimicrobial Agents and Chemotherapy. 47 (5): 1589–97. doi:10.1128/AAC.47.5.1589-1597.2003. PMC   153340 . PMID   12709327.
  2. Schindler CA, Schuhardt VT (Mar 1964). "Lysostaphin: A New Bacteriolytic Agent for the Staphylococcus". Proceedings of the National Academy of Sciences of the United States of America. 51 (3): 414–21. doi: 10.1073/pnas.51.3.414 . PMC   300087 . PMID   14171453.
  3. 1 2 3 Wu JA, Kusuma C, Mond JJ, Kokai-Kun JF (Nov 2003). "Lysostaphin disrupts Staphylococcus aureus and Staphylococcus epidermidis biofilms on artificial surfaces". Antimicrobial Agents and Chemotherapy. 47 (11): 3407–14. doi:10.1128/AAC.47.11.3407-3414.2003. PMC   253758 . PMID   14576095.
  4. Yang XY, Li CR, Lou RH, Wang YM, Zhang WX, Chen HZ, Huang QS, Han YX, Jiang JD, You XF (Jan 2007). "In vitro activity of recombinant lysostaphin against Staphylococcus aureus isolates from hospitals in Beijing, China". Journal of Medical Microbiology. 56 (Pt 1): 71–6. doi: 10.1099/jmm.0.46788-0 . PMID   17172520.
  5. Dajcs JJ, Hume EB, Moreau JM, Caballero AR, Cannon BM, O'Callaghan RJ (May 2000). "Lysostaphin treatment of methicillin-resistant Staphylococcus aureus keratitis in the rabbit". Investigative Ophthalmology & Visual Science. 41 (6): 1432–7. PMID   10798659.
  6. Aguinaga A, Francés ML, Del Pozo JL, Alonso M, Serrera A, Lasa I, Leiva J (Jun 2011). "Lysostaphin and clarithromycin: a promising combination for the eradication of Staphylococcus aureus biofilms". International Journal of Antimicrobial Agents. 37 (6): 585–7. doi:10.1016/j.ijantimicag.2011.02.009. hdl: 10261/49232 . PMID   21497068.
  7. Belyansky I, Tsirline VB, Martin TR, Klima DA, Heath J, Lincourt AE, Satishkumar R, Vertegel A, Heniford BT (Dec 2011). "The addition of lysostaphin dramatically improves survival, protects porcine biomesh from infection, and improves graft tensile shear strength". The Journal of Surgical Research. 171 (2): 409–15. doi:10.1016/j.jss.2011.04.014. PMID   21696759.