Histatin 5-Inspired Short-Chain Peptides Selectively Combating Pathogenic Fungi with Multifaceted Mechanisms.

Short-chain antifungal peptides (AFPs) inspired by histatin 5 have been designed to address the problem of antifungal drug resistance. These AFPs demonstrate remarkable antifungal activity, with a minimal inhibitory concentration as low as 2 µg mL-1. Notably, these AFPs display a strong preference for targeting fungi rather than bacteria and mammalian cells. This is achieved by binding the histidine-rich domains of the AFPs to the Ssa1/2 proteins in the fungal cell wall, as well as the reduced membrane-disrupting activity due to their low amphiphilicity. These peptides disrupt the nucleus and mitochondria once inside the cells, leading to reactive oxygen species production and cell damage. In a mouse model of vulvovaginal candidiasis, the AFPs demonstrate not only antifungal activity, but also promote the growth of beneficial Lactobacillus spp. This research provides valuable insights for the development of fungus-specific AFPs and offers a promising strategy for the treatment of fungal infectious diseases.

Escherichia coli exopolysaccharides disrupt Pseudomonas aeruginosa biofilm and increase its antibiotic susceptibility.

Pseudomonas aeruginosa (P. aeruginosa) is a major pathogen that causes infectious diseases. It has high tendency to form biofilms, resulting in the failure of traditional antibiotic therapies. Inspired by the phenomenon that co-culture of Escherichia coli (E. coli) and P. aeruginosa leads to a biofilm reduction, we reveal that E. coli exopolysaccharides (EPS) can disrupt P. aeruginosa biofilm and increase its antibiotic susceptibility. The results show that E. coli EPS effectively inhibit biofilm formation and disrupt mature biofilms in P. aeruginosa, Staphylococcus aureus, and E. coli itself. The maximal inhibition and disruption rates against P. aeruginosa biofilm are 40 % and 47 %, respectively. Based on the biofilm-disrupting ability of E. coli EPS, we develop an E. coli EPS/antibiotic combining strategy for the treatment of P. aeruginosa biofilms. The combination with E. coli EPS increases the antibacterial efficiency of tobramycin against P. aeruginosa biofilms in vitro and in vivo. This study provides a promising strategy for treating biofilm infections. STATEMENT OF SIGNIFICANCE: Biofilm formation is a leading cause of chronic infections. It blocks antibiotics, increases antibiotic-tolerance, and aids in immune evasion, thus representing a great challenge in clinic. This study proposes a promising approach to combat pathogenic Pseudomonas aeruginosa (P. aeruginosa) biofilms by combining Escherichia coli exopolysaccharides with antibiotics. This strategy shows high efficiency in different P. aeruginosa stains, including two laboratory strains, PAO1 and ATCC 10145, as well as a clinically acquired carbapenem-resistant strain. In addition, in vivo experiments have shown that this approach is effective against implanted P. aeruginosa biofilms and can prevent systemic inflammation in mice. This strategy offers new possibilities to address the clinical failure of conventional antibiotic therapies for microbial biofilms.

A conserved antigen induces respiratory Th17-mediated broad serotype protection against pneumococcal superinfection.

Several vaccines targeting bacterial pathogens show reduced efficacy upon concurrent viral infection, indicating that a new vaccinology approach is required. To identify antigens for the human pathogen Streptococcus pneumoniae that are effective following influenza infection, we performed CRISPRi-seq in a murine model of superinfection and identified the conserved lafB gene as crucial for virulence. We show that LafB is a membrane-associated, intracellular protein that catalyzes the formation of galactosyl-glucosyl-diacylglycerol, a glycolipid important for cell wall homeostasis. Respiratory vaccination with recombinant LafB, in contrast to subcutaneous vaccination, was highly protective against S. pneumoniae serotypes 2, 15A, and 24F in a murine model. In contrast to standard capsule-based vaccines, protection did not require LafB-specific antibodies but was dependent on airway CD4+ T helper 17 cells. Healthy human individuals can elicit LafB-specific immune responses, indicating LafB antigenicity in humans. Collectively, these findings present a universal pneumococcal vaccine antigen that remains effective following influenza infection.