Health leaders and scientists worldwide consider antibiotic resistance among the world's most dangerous pathogens as one of the biggest threats to global health. Antibiotic resistance has largely been attributed to genetic changes, but the role and recalcitrance of biofilms, largely due to growth state dependent adaptive resistance, is becoming increasingly appreciated. Biofilms are mono- and multi-species microbial communities embedded in an extracellular, protective matrix. In this growth state, bacteria are transcriptionally primed to survive extracellular stresses. Adaptations, affecting metabolism, regulation, surface charge, immune recognition and clearance, allow bacteria to thrive in the human body and withstand antibiotics and the host immune system. Biofilms resist clearance by multiple antibiotics and have a major role in chronic infections, causing more than 65% of all infections. No specific antibiofilm agents have been developed. Thus, there is a pressing need for alternatives to traditional antibiotics that directly inhibit and/or eradicate biofilms. Host defence peptides (HDPs) are small cationic peptides that are part of the innate immune system to both directly kill microbes but also function to modulate the immune response. Specific HDPs and their derivatives demonstrate broad-spectrum activity against biofilms. In vivo biofilm assays show efficacy in abscess, respiratory, in-dwelling device, contact lens and skin infection models. Further progress has been made through the study of ex vivo organoid and air-liquid interface models to better understand human infections and treatment while relieving the burden and complex nature of animal models. These avenues pave the way for a better understanding and treatment of the underlying cause of chronic infections that challenge the healthcare system.
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