Antivirulence is the concept of blocking
virulence factors
Virulence factors (preferably known as pathogenicity factors or effectors in plant science) are cellular structures, molecules and regulatory systems that enable microbial pathogens (bacteria, viruses, fungi, and protozoa) to achieve the followin ...
. In regards to
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typically a few micrometr ...
, 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
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention o ...
, due to the emergence of
multidrug-resistant common
pathogen
In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...
strains (both
gram-negative
Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wa ...
and
gram-positive
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.
Gram-positive bact ...
), 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
An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable di ...
, 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
Virulence factors (preferably known as pathogenicity factors or effectors in plant science) are cellular structures, molecules and regulatory systems that enable microbial pathogens (bacteria, viruses, fungi, and protozoa) to achieve the followin ...
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
Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer me ...
and
exotoxins
An exotoxin is a toxin secreted by bacteria. An exotoxin can cause damage to the host by destroying cells or disrupting normal cellular metabolism. They are highly potent and can cause major damage to the host. Exotoxins may be secreted, or, simi ...
).
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. Gram-positive and Gram-negative pathogens adhere to the host tissues through filamentous organelles known as pili. The pili function on initial bacterial adhesion, invasion and
biofilm
A biofilm comprises any syntrophic consortium 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 ...
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. 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
Peptidoglycan or murein is a unique large macromolecule, a polysaccharide, consisting of sugars and amino acids that forms a mesh-like peptidoglycan layer outside the plasma membrane, the rigid cell wall (murein sacculus) characteristic of most ba ...
, 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. 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''.
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
''Bacillus subtilis'', known also as the hay bacillus or grass bacillus, is a Gram-positive, catalase-positive bacterium, found in soil and the gastrointestinal tract of ruminants, humans and marine sponges. As a member of the genus ''Bacillus ...
'' mutants in WTAs are not able to colonize the host tissue and show a greatly diminished ability to establish infection in animal models.
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
Bezlotoxumab, sold under the brand name Zinplava, is a human monoclonal antibody designed for the prevention of recurrence of ''Clostridioides difficile'' infections.
This drug, along with actoxumab, was developed through Phase II efficacy trial ...
(Zinplava) as a treatment aimed at reducing the recurrence of ''
Clostridium difficile'' infection in patients at high risk of recurrence.
[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]
References
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Virulence factors