Antivirulence

Last updated

Antivirulence is the concept of blocking virulence factors. [1] In regards to bacteria, the idea is to design agents that block virulence rather than kill bacteria en masse, as the current regime results in much more selective pressure (on antibiotic resistance).

Contents

From the early 1950s onwards, a large number of antibiotics, due to the emergence of multidrug-resistant common pathogen strains (both gram-negative and gram-positive), became scarcely effective and not-useful. This scenario has stimulated the research for an alternative strategy focused on agents (antivirulence or antipathogenic agents) aimed to disarm microorganisms cause of infectious disease, without killing or inhibiting the growth of microorganisms themselves and therefore with limited selective pressure to promote the antibiotic resistance phenomenon. The antivirulence strategy needs the knowledge of the pathogenic mechanisms and of the virulence factors that underlie them. Virulence factors are the weapons possessed by pathogens to cause damage to the host, hence they are molecules or bacterial cell structures involved in the various stages of pathogenesis such as adhesion, invasion and colonization and also in the ability to escape host defenses and to injury the host tissues by producing toxic molecules (bacterial endotoxins and exotoxins).

Adhesion

The bacterial adhesion to the host tissues, involving a direct and a specific interaction between bacterial surface molecules and host ligands, is a fundamental step for microbial colonization and infection of both Gram-positive and Gram-negative pathogens. Interfere with adhesion, the first step of pathogenesis, could be an efficient way to prevent or treat infections. [2] Gram-positive and Gram-negative pathogens adhere to the host tissues through filamentous organelles known as pili. [3] The pili function on initial bacterial adhesion, invasion and biofilm formation, has been mainly studied for Gram-negative bacteria. There are some works on the synthesis of pilicides, chemical agents synthesized to target the chaperone–subunit interaction and the chaperone interaction with a protein involved in the biogenesis of the pili in Gram-negative known as fimbrial usher protein. [4] Uropathogenic Escherichia coli (UPEC) is the major aetiological agent of Urinary Tract Infections (UTIs) and is often studied as a model of Gram-negative pathogen for the development of pilicides compounds. Similar structural motifs of pilin components has been found in an important family of Gram-positive surface proteins linked to peptidoglycan, the Microbial Surface Components Recognizing Adhesive Matrix Molecules (MSCRAMMs), able to recognize extracellular matrix proteins of host, such as fibrinogen, fibronectin, and collagen. If we consider the important part played by MSCRAMMs in the first step of Gram-positive pathogenesis and of biofilm formation, new antivirulence agents could be developed by using as a target the enzyme responsible of linking such proteins to cell wall, that is the Sortase A (SrtA), rather than any single surface protein involved in the mechanism of virulence. [5] The SrtA is a membrane-bound cysteine transpeptidase that is responsible, in Gram-positive bacteria, for the covalent anchoring of surface proteins to bacterial cell wall. 3,6-Disubstituted triazolo-thiadiazole compounds are under preclinical evaluation (including animal models) as antivirulence drugs against Staphylococcus aureus . [6] Other cell surface molecules in Gram-positive bacteria, involved in the adhesion process, without cell wall anchorage, are non proteinaceous adhesins like Wall Teichoic acids (WTAs) and lipoteichoic acids. Since WTAs are required for host infection and play important role in biofilm formation, it has been suggested that they are important virulence factors required for the establishment and spread of infection in a host. Therefore, the enzymes involved in WTAs biosynthesis can be considered as good targets for novel antivirulence agents that interfere with Gram-positive pathogenic process. One possible target is the WTA biosynthetic pathway because strains of S.aureus and Bacillus subtilis mutants in WTAs are not able to colonize the host tissue and show a greatly diminished ability to establish infection in animal models. [7]

Approved antivirulence drugs

Early examples of the antivirulence approach include mainly the inactivation of bacterial toxins with anti-toxin antibodies administered to post-exposure patients (serological therapy that induces artificially acquired passive immunization). Since inactivation of toxin during infection has proven to be an effective way to prevent or alleviate the symptoms of acute disease, significant progress has been made in the development of novel anti-toxic monoclonal antibodies. Therefore, in October 2016 the US Food and Drug Administration (FDA) and in July 2018 the Italian Drug Agency (AIFA) approved the therapeutic use of a monoclonal antibody called bezlotoxumab (Zinplava) as a treatment aimed at reducing the recurrence of Clostridioides difficile infection in patients at high risk of recurrence. [8]

Related Research Articles

<span class="mw-page-title-main">Pilus</span> A proteinaceous hair-like appendage on the surface of bacteria

A pilus is a hair-like cell-surface appendage found on many bacteria and archaea. The terms pilus and fimbria can be used interchangeably, although some researchers reserve the term pilus for the appendage required for bacterial conjugation. All conjugative pili are primarily composed of pilin – fibrous proteins, which are oligomeric.

<span class="mw-page-title-main">Biofilm</span> Aggregation of bacteria or cells on a surface

A biofilm is a syntrophic community of microorganisms in which cells stick to each other and often also to a surface. These adherent cells become embedded within a slimy extracellular matrix that is composed of extracellular polymeric substances (EPSs). The cells within the biofilm produce the EPS components, which are typically a polymeric combination of extracellular polysaccharides, proteins, lipids and DNA. Because they have a three-dimensional structure and represent a community lifestyle for microorganisms, they have been metaphorically described as "cities for microbes".

<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, meaning that it can grow without 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). The bacterium is a worldwide problem in clinical medicine. Despite much research and development, no vaccine for S. aureus has been approved.

Virulence is a pathogen's or microorganism's ability to cause damage to a host.

<span class="mw-page-title-main">Secretion</span> Controlled release of substances by cells or tissues

Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classical mechanism of cell secretion is via secretory portals at the plasma membrane called porosomes. Porosomes are permanent cup-shaped lipoprotein structures embedded in the cell membrane, where secretory vesicles transiently dock and fuse to release intra-vesicular contents from the cell.

The periplasm is a concentrated gel-like matrix in the space between the inner cytoplasmic membrane and the bacterial outer membrane called the periplasmic space in Gram-negative bacteria. Using cryo-electron microscopy it has been found that a much smaller periplasmic space is also present in Gram-positive bacteria, between cell wall and the plasma membrane. The periplasm may constitute up to 40% of the total cell volume of gram-negative bacteria, but is a much smaller percentage in gram-positive bacteria.

<i>Legionella pneumophila</i> Species of bacterium

Legionella pneumophila is an aerobic, pleomorphic, flagellated, non-spore-forming, Gram-negative bacterium. There are fourteen serotypes of L. pneumophila.L. pneumophila is a facultative intracellular parasite that infects soil amoebae and freshwater amoeboflagellates for replication. This pathogen is thus found commonly near freshwater environments and invades the unicellular life, using them to carry out metabolic functions. Due to L. pneumophila’s ability to thrive in water, it can grow in water filtration systems, leading to faucets, showers, and other fixtures and then spread through aerosolized water droplets.

A slime layer in bacteria is an easily removable, unorganized layer of extracellular material that surrounds bacteria cells. Specifically, this consists mostly of exopolysaccharides, glycoproteins, and glycolipids. Therefore, the slime layer is considered as a subset of glycocalyx.

Bacterial adhesins are cell-surface components or appendages of bacteria that facilitate adhesion or adherence to other cells or to surfaces, usually in the host they are infecting or living in. Adhesins are a type of virulence factor.

<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.

Virulence factors are cellular structures, molecules and regulatory systems that enable microbial pathogens to achieve the following:

Pilin refers to a class of fibrous proteins that are found in pilus structures in bacteria. These structures can be used for the exchange of genetic material, or as a cell adhesion mechanism. Although not all bacteria have pili or fimbriae, bacterial pathogens often use their fimbriae to attach to host cells. In Gram-negative bacteria, where pili are more common, individual pilin molecules are linked by noncovalent protein-protein interactions, while Gram-positive bacteria often have polymerized LPXTG pilin.

<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.

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.

Sortases are membrane anchored enzyme that sort these surface proteins onto the bacterial cell surface and anchor them to the peptidoglycan. There are different types of sortases and each catalyse the anchoring of different proteins to cell walls.

<span class="mw-page-title-main">Outer membrane vesicle</span> Vesicles released from the outer membranes of Gram-negative bacteria

Outer membrane vesicles (OMVs) are vesicles released from the outer membranes of Gram-negative bacteria. While Gram-positive bacteria release vesicles as well, those vesicles fall under the broader category of bacterial membrane vesicles (MVs). OMVs were the first MVs to be discovered, and are distinguished from outer inner membrane vesicles (OIMVs), which are gram-negative bacterial vesicles containing portions of both the outer and inner bacterial membrane. Outer membrane vesicles were first discovered and characterized using transmission-electron microscopy by Indian Scientist Prof. Smriti Narayan Chatterjee and J. Das in 1966-67. OMVs are ascribed the functionality to provide a manner to communicate among themselves, with other microorganisms in their environment and with the host. These vesicles are involved in trafficking bacterial cell signaling biochemicals, which may include DNA, RNA, proteins, endotoxins and allied virulence molecules. This communication happens in microbial cultures in oceans, inside animals, plants and even inside the human body.

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">Bacterial secretion system</span> Protein complexes present on the cell membranes of bacteria for secretion of substances

Bacterial secretion systems are protein complexes present on the cell membranes of bacteria for secretion of substances. Specifically, they are the cellular devices used by pathogenic bacteria to secrete their virulence factors to invade the host cells. They can be classified into different types based on their specific structure, composition and activity. Generally, proteins can be secreted through two different processes. One process is a one-step mechanism in which proteins from the cytoplasm of bacteria are transported and delivered directly through the cell membrane into the host cell. Another involves a two-step activity in which the proteins are first transported out of the inner cell membrane, then deposited in the periplasm, and finally through the outer cell membrane into the host cell.

P fimbriae are chaperone-usher type fimbrial appendages found on the surface of many Escherichia coli bacteria. The P fimbriae is considered to be one of the most important virulence factor in uropathogenic E. coli and plays an important role in upper urinary tract infections. P fimbriae mediate adherence to host cells, a key event in the pathogenesis of urinary tract infections.

Harry Lee Thompson Mobley, Ph.D, is the Frederick G. Novy Distinguished University Professor of Microbiology and Immunology at the University of Michigan Medical School. His research focused on elucidating the mechanisms by which Gram-negative bacilli that include E. coli, Proteus mirabilis, Klebsiella pneumoniae, Citrobacter freundii, Serratia marcescens, Acinetobacter baumannii, and Helicobacter pylori colonize initial sites of infections that include the urinary tract, the lungs, and the gastrointestinal tract, in some cases, disseminating systemically and entering the bloodstream and the blood-filtering organs including the spleen and liver. For decades, the lab studied urinary tract infection including both “uncomplicated” UTI in otherwise healthy women and “complicated” UTI such as catheter-associated UTI. Bacterial infections of the bladder can ascend to the kidneys and enter renal capillaries to gain access to the bloodstream and infect blood-filtering organs. His research focused on the mechanism by which Gram-negative bacilli colonize the human host, elude the innate immune response, and disseminate from primary sites of infection including the urinary tract into the bloodstream.

References

  1. ↑ "Two-for-one bacterial virulence factor revealed". phys.org. Retrieved 17 January 2016.
  2. ↑ Cascioferro, S., Totsika, M., & Schillaci, D. (2014). Sortase A: An ideal target for anti-virulence drug development. Microbial Pathogenesis, 77, 105-112. doi:10.1016/j.micpath.2014.10.007
  3. ↑ Pinkner JS, Remaut H, Buelens F, Miller E, Aberg V, et al. (2006) Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria.Proc Natl Acad Sci U S A 103: 17897-17902.
  4. ↑ Piatek R, Zalewska-Piatek B, Dzierzbicka K, Makowiec S, Pilipczuk J, et al.(2013) Pilicides inhibit the FGL chaperone/usher assisted biogenesis of thefimbrial polyadhesin from uropathogenic Escherichia coli. BMC Microbiol13: 131.
  5. ↑ Cascioferro, S., Raffa, D., Maggio, B., Raimondi, M. V., Schillaci, D., & Daidone, G. (2015). Sortase A inhibitors: Recent advances and future perspectives. Journal of Medicinal Chemistry, 58(23), 9108-9123. doi:10.1021/acs.jmedchem.5b00779
  6. ↑ Zhang J. et al., Antiinfective therapy with a small molecule inhibitor of Staphylococcus aureus sortase, PNAS 16, 2014, 111(37)13517-13522
  7. ↑ Swoboda JG, Campbell J, Meredith TC, Walker S (2010) Wall teichoic acid function, biosynthesis, and inhibition. ChemBioChem 11: 35-45.
  8. ↑ Dickey, S.W, Cheung, G.Y.C, Otto, M. Different drugs for bad bugs: antivirulence strategies in the age of antibiotic resistance. Nature Reviews Drug Discovery 16(7), 457-471, 2017
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.