Critical Parameters for the Development of Novel Therapies for Severe and Resistant Infections—A Case Study on CAL02, a Non-Traditional Broad-Spectrum Anti-Virulence Drug

Abstract

Background: Poor outcomes in severe and resistant infections, together with the economic struggles of companies active in the field of anti-infective development, call for new solutions and front runners with novel approaches. Among “non-traditional” approaches, blocking virulence could be a game changer. Objectives: This review offers a perspective on parameters that have determined the development path of CAL02, a novel anti-virulence agent, with a view to steering clear of the obstacles and limitations that impede market sustainability for new anti-infective drugs. Conclusions and implications of key findings: This case study highlights four pillars that may support the development of other non-traditional drugs and, concurrently, provide a new model that could reshape the field. Therapeutic triggers, study designs, and economic parameters are discussed.

Towards Robust Delivery of Antimicrobial Peptides to Combat Bacterial Resistance

“…Interestingly, certain lipid nanostructures, such as liposomes, reconstituted lipoproteins, and cell membrane-derived nanostructures, have also recently gained attention as "nanodecoys" to trap and restrain pathogens and their toxins to treat infectious diseases [86], potentially providing another advantage for AMP formulation. An example of these agents is CAL02, a clinically tested liposomal antivirulence drug that entraps and neutralizes a large array of virulence factors produced by both Gram-positive and Gram-negative bacteria [87]. By mimicking the cell membrane lipid composition that many virulence effectors target, these liposomes can bind to these toxins with higher affinity than cells, thereby preventing the threatening complications these molecules are associated with during severe infections (e.g., tissue damage and organ failure).…”

Targeted Protein Degradation: The New Frontier of Antimicrobial Discovery?

“…75 Numerous bacteria utilize similar secreted proteins to exploit the autophagy-lysosome pathway and rely on this mechanism to establish intracellular infections. 59 Designing agents to target and degrade intracellularly located bacterial exotoxins based on ubiquitin-dependent PROTACstyle chimeric antibacterial agents would complement existing strategies that sequester bacterial exotoxins, 76 offering the prospect of restoring the host's native defense system against intracellular infection (Figure 4, (ii)).…”

“…Antivirulence agents are currently under investigation as a nontraditional approach to antimicrobial therapy, with the potential to disarm the ability of bacteria to disrupt cell barriers, subdue host immune defenses, and damage tissues and organs. 76,80 Lacking direct intrinsic activity, antivirulence drugs rely on the host immune system and/or adjuvant antibiotic therapies to facilitate clearance of the neutralized infection, emphasizing the importance of rapid diagnosis and treatment. An antivirulence degrader could be pursued in a similar vein to the LYTAC strategy, engaging cell-surface lysosome receptors to induce lysosomal degradation of lethal bacterial toxins before they can act on the host.…”

“…Adapting the LYTAC concept to design antimicrobial degraders targeting extracellular secreted virulence factors or bacterial membrane-bound proteins prior to the establishment of an intracellular infection would complement the PROTAC style approach, with the potential for early neutralization of bacterial pathogenicity (Figure , (iv)). Antivirulence agents are currently under investigation as a nontraditional approach to antimicrobial therapy, with the potential to disarm the ability of bacteria to disrupt cell barriers, subdue host immune defenses, and damage tissues and organs. , Lacking direct intrinsic activity, antivirulence drugs rely on the host immune system and/or adjuvant antibiotic therapies to facilitate clearance of the neutralized infection, emphasizing the importance of rapid diagnosis and treatment. An antivirulence degrader could be pursued in a similar vein to the LYTAC strategy, engaging cell-surface lysosome receptors to induce lysosomal degradation of lethal bacterial toxins before they can act on the host.…”

Nontraditional Antibiotics—Challenges and Triumphs

“…The concept paper by Azeredo da Silveira and Shorr provides an excellent case study on CAL02, a liposome-derived anti-virulence trap designed to sequester bacterial toxins by acting as a decoy mimic of cellular lipid platforms [4]. The three review articles by Zurawski and McLendon [5], Nikolich and Filippov [6], and Ghose and Euler [7] give a superb timely survey of how monoclonal antibodies, bacteriophages and lysins, respectively, are currently being explored in the treatment of bacterial infections.…”