Stringent response inhibitors: Persistent infections affect many; while they are often asymptomatic, the persisting bacteria may be reactivated at any time to cause renewed infection. The quiescent pathogens are termed "persister bacteria". Many different mechanisms by which persistent infection is thought to be achieved have been proposed and include stringent response, SOS response, 214 toxin-antitoxin response, 215 and oxidative stress response. Stringent response is a mechanism by which bacteria counter extreme nutritional starvation (amino acids, fatty acids, iron) and other stresses that allow for survival. Classified as a stress response, the expression and accumulation of guanosine 5'-diphosphate 3'-diphosphate (ppGpp) and guanosine 5'-triphosphate 3'-diphosphate (pppGpp) are the hallmarks of the stringent response. Both ppGpp and pppGpp, often collectively referred to as (p)ppGpp, are produced by (p)ppGpp synthetase which includes the RelA/SpoT homolog and small alarmone synthetase proteins. The exact mechanism by which these molecules achieve stringent response is thought to be varied, one of which includes binding directly to RNA polymerase leading to decreased transcription. While initially discovered in E. coli, subsequently stringent response has also been identified in many other bacterial species including Mycobacterium 223 and Bacillus. It is now increasingly believed that activation of stringent response might be an important determinant of antibiotic efficacy and might contribute to antibiotic resistance. One avenue that has been explored in recent years, is the use of structurally similar compounds such as 2'-deoxyguanosine-3',5'-di(methylene bisphosphonate), and analogs leading to competitive inhibition of (p)ppGpp synthetase and decreased production of (p)ppGpp 227 putting a halt to further downstream signaling. Other examples of structurally similar analogs of (p)ppGPpp explored as stringent inhibitors include relacin 228 and its derivatives. Peptide-based derivatives that bind to and trigger degradation of (p)ppGpp have also been developed 230 and were shown to be effective against multidrug-resistant ESKAPEE pathogens. In recent years, similar efforts have been made for Mycobacterium tuberculosis by designing small molecule (p)ppGpp synthetase inhibitors based on ppGpp and relacin 233 and identification of novel/new leads by screening a 2 million compound library. Other bacterial strains for whom this avenue is being explored include Neisseria 235 and Bacillus. 236