Legless pathogens: how bacterial physiology provides the key to understanding pathogenicity

Action of nitroheterocyclic drugs against Clostridium difficile

“…Therefore, Hcp appears to have a broader role in responding to cellular damage caused by reactive species and not just in the detoxification of hydroxylamine radicals. This might support the recent hypothesis by Cole [25] that Hcp may be involved in repairing damaged metalloproteins. Furthermore, low induction of hcp by nitazoxanide supports its distinct mode of action as an inhibitor of PFOR activity, which does not involve reduction to reactive species that occur with other nitroheterocyclic drugs.…”

“…However, we are unaware of reports demonstrating that hcp responds to nitroimidazole and nitrofuran drugs. We believe this suggests that there are some intersections in the types of cellular damage caused or proteins targeted by nitroimidazoles, nitrofurans and nitrosating agents [25]. We speculate this overlap primarily occurs at the proteome level, resulting from their respective reactive species either forming adducts or causing damage to similar cellular proteins [25].…”

“…We believe this suggests that there are some intersections in the types of cellular damage caused or proteins targeted by nitroimidazoles, nitrofurans and nitrosating agents [25]. We speculate this overlap primarily occurs at the proteome level, resulting from their respective reactive species either forming adducts or causing damage to similar cellular proteins [25]. Therefore, Hcp appears to have a broader role in responding to cellular damage caused by reactive species and not just in the detoxification of hydroxylamine radicals.…”

Copper Efflux Is Induced during Anaerobic Amino Acid Limitation in Escherichia coli To Protect Iron-Sulfur Cluster Enzymes and Biogenesis

“…However, toxicity originated from the physiological copper reserve, and how bacterial cells counteract the toxicity had not been studied, largely because previous studies focused on the circumstances in which bacterial cells were directly challenged with additional exogenous copper. To our knowledge, our current study is the first to show that the Cus system is induced by the endogenous copper stress that originates from changes of the growth environment of bacteria, i.e., anaerobic amino acid limitation, which is sporadically encountered by bacteria during their colonization in human hosts (3,(14)(15)(16). Since fluctuations of the copper concentration in human hosts, especially the elevation of copper concentrations in the gastrointestinal tract (49), gallbladder, and in macrophages infected with bacteria (50), have been documented, our findings showing that the stress-induced copper homeostasis not only protected metabolic enzymes and thus facilitated the physiological adaptation of E. coli, but also conferred resistance to exogenous copper challenge, suggesting that copper efflux as an important strategy of bacterial physiological adaptation may serve as an important mechanism for bacterial pathogenesis in the human host.…”

“…Sensing various environmental cues and responding to the signals with high efficiency and specificity are essential for the adaption and survival of bacteria (1)(2)(3). To survive the adverse environment of the human gastrointestinal tract, enteric bacteria, such as Escherichia coli, mediate the gene expression involved in many physiological processes, including nutrient acquisition and resistance to noxious compounds derived from host metabolism and immune responses.…”