Antivirulence

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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).

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 Clostridium difficile infection in patients at high risk of recurrence. [8]

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<i>Staphylococcus aureus</i> species of bacterium

Staphylococcus aureus is a Gram-positive, round-shaped bacterium that is a member of the Firmicutes, and it 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. The emergence of antibiotic-resistant strains of S. aureus 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.

Virulence is a pathogen's or microbe's ability to infect or damage a host.

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Aminoglycoside molecule or a portion of a molecule composed of amino-modified sugars

Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside (sugar). The term can also refer more generally to any organic molecule that contains amino sugar substructures. Aminoglycoside antibiotics display bactericidal activity against Gram-negative aerobes and some anaerobic bacilli where resistance has not yet arisen but generally not against Gram-positive and anaerobic Gram-negative bacteria.

Tigecycline chemical compound

Tigecycline is an antibiotic for a number of bacterial infections. It is a glycylcycline 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.

<i>Pseudomonas aeruginosa</i> common bacterium

Pseudomonas aeruginosa is a common encapsulated, Gram-negative, rod-shaped bacterium that can cause disease in plants and animals, including humans. A species of considerable medical importance, P. aeruginosa is a multidrug resistant pathogen recognized for its ubiquity, its intrinsically advanced antibiotic resistance mechanisms, and its association with serious illnesses – hospital-acquired infections such as ventilator-associated pneumonia and various sepsis syndromes.

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

Virulence factors are molecules produced by bacteria, viruses, fungi, and protozoa that add to their effectiveness and enable them to achieve the following:

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β-Lactamase inhibitor Endogenous substances and drugs that inhibit or block the activity of beta-lactamases

Beta-lactamases are a family of enzymes involved in bacterial resistance to beta-lactam antibiotics. They act by breaking the beta-lactam ring that allows penicillin-like antibiotics to work. Strategies for combating this form of resistance have included the development of new beta-lactam antibiotics that are more resistant to cleavage and the development of the class of enzyme inhibitors called beta-lactamase inhibitors. Although β-lactamase inhibitors have little antibiotic activity of their own, they prevent bacterial degradation of beta-lactam antibiotics and thus extend the range of bacteria the drugs are effective against.

Sortase

Sortase refers to a group of prokaryotic enzymes that modify surface proteins by recognizing and cleaving a carboxyl-terminal sorting signal. For most substrates of sortase enzymes, the recognition signal consists of the motif LPXTG (Leu-Pro-any-Thr-Gly), then a highly hydrophobic transmembrane sequence, followed by a cluster of basic residues such as arginine. Cleavage occurs between the Thr and Gly, with transient attachment through the Thr residue to the active site Cys residue, followed by transpeptidation that attaches the protein covalently to cell wall components. Sortases occur in almost all Gram-positive bacteria and the occasional Gram-negative or Archaea, where cell wall LPXTG-mediated decoration has not been reported. Although sortase A, the "housekeeping" sortase, typically acts on many protein targets, other forms of sortase recognize variant forms of the cleavage motif, or that catalyze the assembly of pilins into pili.

Saf pilin N-terminal extension

In molecular biology, the protein domain, Saf pilin N-terminal extension refers to a domain only found in bacteria, more specifically, in gram-negative bacteria. Pili need to be formed by bacteria, as they are a method of adhering to the host organism which helps them infect the host cell. In other words, they are the bacteria's virulence factor. This particular protein domain helps the pili to form, via a complex mechanism named the chaperone/usher pathway. This protein domain is highly important for such bacteria, as without pili formation, they could not infect the host.

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Membrane vesicle trafficking in eukaryotic animal cells involves movement of important biochemical signal molecules from synthesis-and-packaging locations in the Golgi body to specific 'release' locations on the inside of the plasma membrane of the secretory cell, in the form of Golgi membrane-bound micro-sized vesicles, termed membrane vesicles (MVs). In this process, the 'packed' cellular products are released/secreted outside the cell across its plasma membrane. However, this vesicular membrane is retained and recycled by the secretory cells. This phenomenon has a key role in synaptic neurotransmission, endocrine secretion, mucous secretion, granular-product secretion by neutrophils, etc. The scientists behind this discovery were awarded Nobel prize for the year 2013. In the prokaryotic gram-negative bacterial cells, membrane vesicle trafficking is mediated via bacterial outer membrane bounded nano-sized vesicles, called bacterial outer membrane vesicles (OMVs). In this case, however, the OMV membrane is secreted as well, along with OMV-contents to outside the secretion-active bacterium. This phenomenon has a key role in host-pathogen interactions, endotoxic shock in patients, invasion and infection of animals/plants, inter-species bacterial competition, quorum sensing, exocytosis, etc.

Bacterial outer membrane vesicles

Bacterial outer membrane vesicles (OMVs) are vesicles of lipids released from the outer membranes of Gram-negative bacteria. These vesicles were the first bacterial membrane vesicles (MVs) to be discovered, while Gram-positive bacteria release vesicles as well. 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.

Gabriel Waksman FMedSci, FRS, is Courtauld professor of biochemistry and molecular biology at University College London (UCL), and professor of structural and molecular biology at Birkbeck College, University of London. He is the director of the Institute of Structural and Molecular Biology (ISMB) at UCL and Birkbeck, head of the Department of Structural and Molecular Biology at UCL, and head of the Department of Biological Sciences at Birkbeck.

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P fimbriae or P pili or Pap are chaperon-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.

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
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