In a mouse model, infection with an hmp deletion mutant resulted in improved survivability of hosts compared to those infected with wild-type (WT), which indicated that the mutant was less virulent ( Bang et al., 2006).
For instance, in Salmonella enterica, flavohemoglobin, which is encoded by hmp and detoxifies NO by converting it to NO 3 – ( Crawford and Goldberg, 1998 Gardner et al., 1998), has been demonstrated to be critical for virulence ( Stevanin et al., 2002). These strategies include bacteriophages ( Wright et al., 2009 Kutateladze and Adamia, 2010), antimicrobial peptides ( Hancock and Sahl, 2006 Mahlapuu et al., 2016), predatory bacteria that prey on pathogens ( Kadouri et al., 2013), and agents that target virulence factors that are critical for pathogenesis ( Cegelski et al., 2008 Brannon and Hadjifrangiskou, 2016 Dickey et al., 2017 Fleitas Martinez et al., 2019).īacterial defenses responsible for neutralizing nitric oxide (NO), which is synthesized by inducible nitric oxide synthase (iNOS) in phagocytes ( Missall et al., 2004), have been identified in various pathogens to contribute to virulence ( Forrester and Foster, 2012 Robinson et al., 2014). To address these issues, alternative modalities to treat bacterial infections have been proposed and explored ( Clatworthy et al., 2007 Allen et al., 2014 Mahlapuu et al., 2016). Furthermore, increasing occurrences of bacteria resistant to last resort antibiotics indicate the precarious state of the antibiotic arsenal ( Bratu and Eramo, 2005 Kumarasamy et al., 2010 Meletis, 2016). If left unchecked, antibiotic resistance is projected to cause 10 million annual deaths globally and cost the global economy a total of as much as $100 trillion over the next 30 years ( O’Neil, 2014). Infections by resistant pathogens contribute to more than 2.8 million hospitalizations and result in more than 35,000 deaths every year in the US alone ( CDC, 2019). Overall, these results provide a strong foundation for further exploration of 2-MBT and 2-MT for therapeutic applications.Īntibiotic resistance remains a significant threat to modern medicine ( Frieri et al., 2017 The Center for Disease, Dynamics Economics and Policy, 2018). Specifically, 2-MT could still prohibit NO detoxification, though it did not interfere with Hmp catalysis rather, it was a stronger inhibitor of protein synthesis and it reduced the transcript levels of hmp, which was not observed with 2-MBT. Interestingly, when 2-mercaptothiazole (2-MT), which lacked the benzene ring, was used, differing biological activities were observed, although they too were NO dependent. In addition, by studying the structure-activity relationship of 2-MBT, we found that both sulfur atoms in 2-MBT were vital for its inhibition of NO detoxification. Further analysis revealed that in the presence of NO, 2-MBT impaired the catalysis of Hmp and synthesis of Hmp and other proteins, whereas in its absence there were minimal perturbations to growth and protein synthesis. We found that 2-mercaptobenzothiazole (2-MBT) can potently inhibit cellular detoxification of NO, achieving a level of inhibition that resembled the effect of genetically removing Hmp, the dominant detoxification enzyme under oxygenated conditions. In this study, we performed chemical screens to identify inhibitors of NO detoxification in Escherichia coli. Nitric oxide (NO) defense systems have been identified as critical for the pathogenesis of various bacteria, making them an appealing therapeutic target. Among them, anti-virulence therapies, which target pathways important for virulence, have attracted much attention. To reinforce the anti-infective arsenal, many novel therapeutic strategies to fight bacterial infections are being explored. 4Small Molecule Screening Center, Princeton University, Princeton, NJ, United StatesĪntibiotic resistance poses a serious threat to global health.3Department of Molecular Biology, Princeton University, Princeton, NJ, United States.2Frick Chemistry Laboratory, Department of Chemistry, Princeton University, Princeton, NJ, United States.1Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ, United States.James Link 1,2,3, Hahn Kim 2,4 and Mark P. Wen Kang Chou 1, Mathini Vaikunthan 1, Hendrik V.
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