The Synergistic Effect of Exogenous Glutamine and Rifampicin Against Mycobacterium Persisters

Abstract

Persisters, stochastic dormant variants of normal bacteria cell, represent a significant portion of the survivors upon exposure to antibiotics and other environmental stresses, which contributes substantially to high level antibiotics tolerance. Glutamine is a crucial component of the Mycobacteria nitrogen pool that is indispensable for survival upon stresses. To study whether a synergistic effect exists between glutamine and antibiotics against Mycobacterial persisters, the efficacy of rifampicin alone or together with exogenous glutamine upon Mycobacterium smegmatis mc2 155 persisters was monitored. The result showed that glutamine decreases M. smegmatis tolerance to rifampicin upon starvation. The reactive oxygen species level of the strains treated with rifampicin and glutamine increased. The synergism of glutamine and rifampicin to kill persisters might derive from altering the oxidative phosphorylation and TCA cycle, as both evidenced by both ATP level increase and transcriptome change. Glutamine might represent a synergistic agent of rifampicin to kill Mycobacteria persisters.

Transcriptional Shift and Metabolic Adaptations during Leishmania Quiescence Using Stationary Phase and Drug Pressure as Models

“…In promastigotes, GP63 increases during the transition to the stationary phase, and is abundant in the infective non-proliferative metacyclics [66,67]. Upon transmission to a mammalian host, GP63 plays a key role in the evasion and inactivation of the host's innate immune system [68]. In L. major, GP63 modulates the normal course of phagocytosis by hampering the acidification of the phagolysosome [69], and it also prevents the ROS burst by proteolytically impairing the assembly of the NOX2 complex [68].…”

Transcriptional shift and metabolic adaptations during Leishmania quiescence using stationary-phase and drug pressure as models

“…A closer inspection in promastigotes and amastigotes revealed that at a transcriptional level only quiescent cells under PAT pressure downregulate four proteins related to the amino acid permease family, which suggests that decreased amino acid intake could be an important mechanism of regulation. A low level of amino acids is a hallmark of quiescence among bacteria and in Mycobacterium, the addition of glutamine sensitises quiescent forms to rifampicin since it alters their TCA cycle [64]. Against the overall down trend, quiescent cells across conditions had a clear increase in polyhexoses inferred to be part of the mannogen complex in these parasites, and a carbohydrate reserve already shown to be increased in stationary promastigotes and quiescent amastigotes of L. mexicana [32,65].…”

Aureolic Acid Group of Agents as Potential Antituberculosis Drugs

“…As a result of such changes, reactive oxygen species (ROS) accumulate in the cell, since they are formed mainly through the transfer of electrons along the respiratory chain and the conversion of NADH into NAD+ [ 25 ]. In turn, changes in the NAD+/NADH ratio may imbalance intracellular redox potential [ 26 ]. This is also evidenced by the increased transcription of the genes encoding the ATP-binding transporters ( MSMEG_5008 , MSMEG_6046 , MSMEG_6052 , MSMEG_1640 ) and ATPases ( MSMEG_0615 , MSMEG_5044 , MSMEG_6058 ).…”