Natural compounds as anti-virulence agents and in combination with antibiotics to combat multi-resistant pathogens

Antibiotics are a cornerstone of modern medicine. However, there is now the serious problem that bacterial resistance exists against almost all available antibiotics. Infections with multi-resistant ESKAPE pathogens like Escherichia coli or Pseudomonas aeruginosa can no longer be treated reliably. Among others, therapeutic strategies like phage therapy, competitive exclusion, or anti-virulence drugs could be alternatives for non-life-threatening infections. Multidrug-resistant pathogenic clonal lineages, such as ESBL-producing E. coli ST131, possess many virulence factors that significantly contribute to their success. This also means that weakening these factors can dramatically reduce the pathogens' success. Identified virulence factors include adhesins , siderophores, toxins, protectins, and biofilm formation abilities. Interestingly, targeting these structures does not quickly lead to bacterial resistance or cross-resistance to other antibiotics. This means antivirulence agents impair the pathogenic potential of bacteria without being bactericidal, allowing the host's immune system to eliminate the pathogen. Overall, the use of antivirulence agents is expected to exert less selective pressure on pathogens compared to traditional antibiotics. Natural compounds hold great potential for the development of new drugs due to millions of years of co-evolution, which have conditioned small natural compounds for interaction with living systems, highlighting their potential for the development of new anti-infectives. In recent years, numerous natural compounds such as wedenolactone and EGCG have been identified that can inhibit biofilm formation of multidrug-resistant pathogens. This process has been accelerated by the use of machine learning approaches. Additionally, natural compounds have been identified that show strong synergistic effects with conventional antibiotics, making ESKAPE pathogens sensitive to some antibiotics again. For instance, ciprofloxacin-resistant P. aeruginosa responded sensitively to ciprofloxacin when co-administered with myricetin. The rapid bacteriostatic or bactericidal effect of antibiotics has revolutionized medicine and will continue to be indispensable for severe infections in the future. However, new agents can help use conventional antibiotics more selectively and sparingly by providing alternatives for the treatment and prevention of relatively mild urinary tract infections, for example.