Superbugs' resistivity against available natural products has become an alarming global threat, causing a rapid deterioration in public health and claiming tens of thousands of lives yearly. Although the rapid discovery of small molecules from plant and microbial origin with enhanced bioactivity has provided us with some hope, a rapid hike in the resistivity of superbugs has proven to be the biggest therapeutic hurdle of all times. Moreover, several distinct mechanisms endowed by these notorious superbugs make them immune to these antibiotics subsequently causing our antibiotic wardrobe to be obsolete. In this unfortunate situation, though the time frame for discovering novel "hit molecules" down the line remains largely unknown, our small hope and untiring efforts injected in hunting novel chemical scaffolds with unique molecular targets using high-throughput technologies may safeguard us against these life-threatening challenges to some extent. Amid this crisis, the current comprehensive review highlights the present status of knowledge, our search for bacteria Achilles' heel, distinct molecular signaling that an opportunistic pathogen bestows to trespass the toxicity of antibiotics, and facile strategies and appealing therapeutic targets of novel drugs. Herein, we also discuss multidimensional strategies to combat antimicrobial resistance.
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