The widespread emergence and the inevitable rise of antimicrobial resistance are posing a great threat to human health, which contributes to the major health crisis to be combated globally. Biofilms are attached aggregates of microorganisms that can induce biocorrosion, biofouling, and biofilm-associated diseases, rendering cells much more resistant, persistent, resilient, and also easier to develop resistance than their planktonic counterparts. With the increase in biofilm-associated problems, however, efficient biofilm control approaches are limited, increasing the risks in resistance development. Traditional drug discovery mainly focuses on planktonic cells, therefore, resulting in the delayed development of antibiofilm agents. With the urgent and great demand, antibiofilm agents hav...[ Read more ]

The widespread emergence and the inevitable rise of antimicrobial resistance are posing a great threat to human health, which contributes to the major health crisis to be combated globally. Biofilms are attached aggregates of microorganisms that can induce biocorrosion, biofouling, and biofilm-associated diseases, rendering cells much more resistant, persistent, resilient, and also easier to develop resistance than their planktonic counterparts. With the increase in biofilm-associated problems, however, efficient biofilm control approaches are limited, increasing the risks in resistance development. Traditional drug discovery mainly focuses on planktonic cells, therefore, resulting in the delayed development of antibiofilm agents. With the urgent and great demand, antibiofilm agents have been highly sought after. However, drug discovery has been stuck by years of disinvestment from the industry. Historically, most of the drugs were sourced from natural products or their derivatives, but the skyrocketing costs and continuous rediscovery of known compounds made pharmaceutical companies scale back or abandon their screening program for bioactive natural products one after another. Innovative drug discovery strategies are needed to be developed and high-throughput screening of synthetical chemical libraries directed at molecular targets has been widely employed, yet, failure in producing new drugs through this approach and the vast unexplored bioactivity of natural products revealed by advanced biotechnology attract research interest back to natural products. In the present study, we aim to search for compounds that possess specific activities against biofilms from natural products to control biofilm-associated problems. A series of criteria were set accordingly based on the characteristics of biofilms to screen for compounds against biofilm-associated diseases and marine biofilm development. Elasnn produced by Streptomyces mobaraensis DSM 40847 was consequently isolated and identified to be a potential antibiofilm agent for controlling MRSA biofilm-associated infection and preventing marine biofilm/biofouling development. Elasnin was then assessed for toxicity, resistance development, and bioactivity compared with commercial products for specific problems respectively, which supported its safety and efficiency for further application. Therefore, comprehensive mechanism studies consisting of multi-omics analysis, cell-staining, microscopic imaging, gene engineering, in-silicon study, and various bioassays were employed for elucidating the mode of action of elasnin against mono-species MRSA biofilm and multi-species marine natural biofilm, and applications of elanin in simulated models and realistic situations were also conducted simultaneously. Results revealed that elasnin acts as a signal molecule in the biofilms and interfered with cells’ self-regulations and cell-cell communications, therefore, intervening in biofilm development without killing them. The high safety and efficiency, as well as low resistance developmental risk of elasnin, confirmed the validity of antibiofilm agents as a strong tool for fighting against antimicrobial resistance and highlighted the advantages of using signal molecules for developing new antimicrobial strategies. Overall, this study gives a full picture of how an antibiofilm agent was discovered and developed for fighting against microbial resistance. New insights into biofilm development and prevention were also provided with a deeper and more comprehensive understanding of the regulation and communication among the microbial community, contributing to the innovation and development of drug discovery strategy in the resistance era.