Antibiotic resistance is one of the most serious challenges that the world is currently facing. The number of people succumbing to drug-resistant infections is increasing every day, but the rate of drug discovery has failed to match the requisite demands. Most of the currently known antibiotics target the three essential pathways of central dogma. However, bacteria have evolved multiple mechanisms to survive these antibiotics. Consequently, there is an urgent necessity to target auxiliary pathways for the discovery of new drugs. Metabolism-related and stress-associated pathways are ideal in this regard. The stringent response pathway regulated by the signaling nucleotides (p)ppGpp is an attractive target as inhibition of the pathway would in turn decrease the persistence and long-term survival of pathogenic bacteria. In this perspective, we focus on the recent design of small molecule analogues of (p)ppGpp that have yielded promising results in terms of growth and biofilm inhibition. Additionally, we discuss how targeting small RNAs and riboswitches, as well as antimicrobial peptides, would help combat drug-resistant infections in the near future.
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