Heterocyclic scaffolds in antibiofilm strategies against drug-resistant pathogens: a comprehensive review

Background: Antimicrobial resistance (AMR) is a primary global health concern, exacerbated by the ability of drug-resistant pathogens to form biofilms. These biofilms, which harbor microbial communities embedded in an extracellular polymeric matrix (EPS), enhance antibiotic resistance and immune responses, leading to persistent infections. Heterocyclic compounds have shown significant potential in combating biofilm-associated infections due to their structural diversity and mechanisms of action. Methodology: This review systematically examines the antibiofilm potential of various heterocyclic scaffolds, including imidazoles, pyrazoles, indoles, quinolines, coumarins, and select six-membered heterocycles (pyridine, morpholine, piperazine). Studies were analyzed based on their mechanisms of action, structure-activity relationships (SAR), and synergy with conventional antibiotics. Result and Discussion: Imidazole derivatives disrupted biofilm integrity and enhanced antibiotic susceptibility in Pseudomonas aeruginosa and Staphylococcus aureus, with IC50 values ranging from 0.53 to 9.5 µM. Pyrazole-based compounds inhibited Staphylococcus epidermidis biofilms, with IC50 values ranging from 3.1 to 15.6 µg/mL. Indole derivatives, particularly pyrroloindoline triazole amides, inhibited MRSA biofilms with IC50 values as low as 2.8 µM by targeting quorum sensing and curli production. Quinoline compounds demonstrated greater than 90% inhibition of E. coli and P. aeruginosa biofilms and showed synergistic effects with antibiotics. Conclusion: Heterocyclic compounds exhibit promising antibiofilm activity, presenting a viable approach to overcoming AMR. These compounds not only disrupt biofilm formation but also enhance the efficacy of conventional antibiotics through synergistic interactions. Such synergy potentiates the antimicrobial effect by improving antibiotic penetration or disrupting resistance pathways. Future research should focus on optimizing pharmacokinetics and exploring these synergistic combinations to improve clinical applicability.