A novel strategy for combating multidrug-resistant bacteria: Natural products from uncultured microorganisms.

The emergence of bacterial resistance has severely compromised the efficacy of antibiotics, creating an urgent public health crisis. Regrettably, conventional natural products (NPs), nature's primary reservoir for antibiotic discovery, are being exhausted due to overexploitation, leading to a concerning scarcity of developable NPs. There is an urgent need for new strategies to combat infections caused by drug-resistant bacteria. Of particular significance is the emerging recognition that the uncultured microbial majority in natural environments may synthesize antimicrobial compounds with unprecedented structural motifs and functional attributes capable of bypassing existing cross-resistance patterns, thereby maintaining potency against resistant pathogens-a revelation that reinvigorates the therapeutic pipeline with newfound optimism. Here, this review comprehensively and systematically expounds the newest methods for cultivating uncultured microorganisms and the action mechanisms of antibiotics from uncultured microorganisms in recent years. These antibiotics effectively bypass the multidrug resistance barrier, demonstrate excellent antibacterial activity, and show minimal resistance at present. Furthermore, they have served as novel chemical scaffolds for the development of numerous derivatives with good antibacterial activity. In summary, these antibiotics are highly unique, indicating strong potential for development and application. The NPs from uncultured microorganisms hold a great promise in addressing the issue of antibiotic resistance, providing strategic directions for the development of novel antimicrobial drugs and alleviating the resistance crisis.