Antimicrobial resistance (AMR) is a global health challenge, with an estimated 10 million deaths annually by 2050 if left unabated. Identifying new sources for developing effective drugs against pathogenic microbes, including drug-resistant infections, is crucial. Natural products, especially from extreme habitats with rich biodiversity, are considerably more effective than synthetic compounds. Thermophiles in deserts, volcanic regions, hot springs, and hydrothermal vents produce novel and vital bioactive compounds (BACs), such as antimicrobial agents (AMAs) and antimicrobial peptides (AMPs). Due to their extreme environments, thermophilic bacteria exhibit unique features in their morphology, physiology, biochemistry, and molecular mechanisms, leading to exceptional chemical structures and biological activities applicable in different biotechnological applications. This review therefore aims to provide an overview of thermophilic bacteria from various global regions and their physiological and adaptive features in extremely hot environments. Also, it summarizes their production of AMAs and AMPs, focusing on key bacterial genera that produce AMAs, such as Actinomycetes, Bacillus, and Geobacillus, and also highlighting the classification and mechanisms of thermostable AMPs. In addition, it includes examples from Saudi Arabia to illustrate regional research progress and potential. Furthermore, the review discusses current limitations and future perspectives regarding the biotechnological applications of thermophilic bacteria. The remarkable efficacy of thermophilic-derived BACs offers promising opportunities for innovation and development in medicine, agriculture, and food applications.
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