Development of Anti-Virulence Therapeutics against Mono-ADP-Ribosyltransferase Toxins

Abstract

Mono-ADP-ribosyltransferase toxins are often key virulence factors produced by pathogenic bacteria as tools to compromise the target host cell. These toxins are enzymes that use host cellular NAD+ as the substrate to modify a critical macromolecule target in the host cell machinery. This post-translational modification of the target macromolecule (usually protein or DNA) acts like a switch to turn the target activity on or off resulting in impairment of a critical process or pathway in the host. One approach to stymie bacterial pathogens is to curtail the toxic action of these factors by designing small molecules that bind tightly to the enzyme active site and prevent catalytic function. The inactivation of these toxins/enzymes is targeted for the site of action within the host cell and small molecule therapeutics can function as anti-virulence agents by disarming the pathogen. This represents an alternative strategy to antibiotic therapy with the potential as a paradigm shift that may circumvent multi-drug resistance in the offending microbe. In this review, work that has been accomplished during the past two decades on this approach to develop anti-virulence compounds against mono-ADP-ribosyltransferase toxins will be discussed.

The DarT/DarG Toxin–Antitoxin ADP-Ribosylation System as a Novel Target for a Rational Design of Innovative Antimicrobial Strategies

“…In the last two decades, antimicrobial strategies against ADP-ribosylating toxins have been proposed given that they are expected to provide new drug targets to disarm antibiotic-resistant bacteria. Different strategies, starting from the combination of PARP inhibitors, have been tested on P. aeruginosa Exotoxin A, V. cholerae Cholix toxin, V. splendidus Vis toxin, S. scabies Scabin toxin, Bacillus cereus Certhrax toxin, Paenibacillus larvae C3larvin, and Plx2A ([ 175 ] and the references therein). Such strategies have been searched for using ARTD non-specific inhibitors such as PJ34 [ 176 ], largely known for targeting human ARTDs (i.e., PARPs), polyphenolic extracts [ 177 ], and small molecules from the screening of synthetic libraries [ 178 , 179 , 180 ].…”

Anti-Virulence Strategy against the Honey Bee Pathogenic Bacterium Paenibacillus larvae via Small Molecule Inhibitors of the Bacterial Toxin Plx2A

“…In such an anti-virulence therapeutic approach, the pathogen only gets disarmed and not killed, and thus this strategy circumvents the direct selection pressure on the pathogen to produce resistant strains. Blocking bacterial virulence factors with small molecule inhibitors is therefore considered one possible strategy to combat bacterial infections as an alternative to antibiotics in the emerging field of antibiotic resistance (as reviewed by [ 67 , 68 , 69 , 70 , 71 ]). A further advantage of virulence factor inhibition is that the microbiome of the host does not get affected, in contrast to the use of antibiotics.…”

“…Furthermore, targeting virulence factors also broadens the repertoire of bacterial targets by not only affecting essential factors for growth and survival of the pathogen (as reviewed by [ 67 , 68 ]). Strategies for the virulence inhibition currently under investigation are (i) the interference in the regulation of virulence factor expression, (ii) the interference in systems involved in virulence factor assembly, (iii) the interference in biofilm formation and bacterial adhesion, and (iv) a direct interference with the virulence factors such as the inhibition of bacterial toxin function or toxin delivery (see reviews by [ 67 , 68 , 69 , 70 ] and references therein). Compounds used for the inhibition of virulence factors already described include antibodies, nanoparticles, bioactive peptides, and small molecules, the latter being either synthetics screened from chemical libraries or natural compounds derived from plant extracts (as reviewed by [ 69 ]).…”

A Structural Approach to Anti-Virulence: A Discovery Pipeline

“…Thus, the "anti-infective" agent/drug interferes with the pathogen's ability to cause disease [14,15]. One avenue for this approach is to target bacterial toxins using this powerful method [9,[16][17][18][19]. This approach involves the use of patho-or virulence blockers developed specifically to bind bacterial virulence factors with high affinity, neutralizing or reducing the virulence of the offending pathogen [17,20,21].…”