Novel endogenous protein-based strategies to inhibit clinically relevant bacterial AB-type toxins including pertussis toxin

Many highly infectious and severe diseases such as pertussis, diphtheria, anthrax, and Clostridioides difficile infections are caused by bacteria which release symptom-inducing AB-type protein toxins. These diseases are treated using antibiotics or preventive measures including vaccination. However, despite preventive measures, increasing case numbers have been reported in past years. Therefore, novel therapeutic options against toxin-mediated disease are urgently required. Since the toxins are the causative agents of the diseases, the development of pharmacological inhibitors that specifically neutralize individual toxins should be a relevant strategy to further support the current therapies. Huge potential to identify toxin inhibitors lies within the human proteome/peptidome that might contain endogenous toxin inhibitors as yet unknown part of the innate immunity. Screening of human peptide libraries and systematic testing of proteins/peptides with antimicrobial activity led to the identification of proteins/peptides with specific anti-toxin activities. Consequently, defensins, α1-antitrypsin and derived peptides, human serum albumin, and in silico predicted angiogenin-derived peptides were identified as potent inhibitors for bacterial toxins including Clostridioides difficile toxins TcdA, TcdB and CDT, diphtheria, anthrax, and pertussis toxin, and clostridial binary iota and C2 toxins. This review summarizes the current state of identified endogenous proteins/peptides as novel inhibitors for clinically relevant bacterial AB-type toxins.