Iron Deprivation Affects Drug Susceptibilities of Mycobacteria Targeting Membrane Integrity

Abstract

Multidrug resistance (MDR) acquired by Mycobacterium tuberculosis (MTB) through continuous deployment of antitubercular drugs warrants immediate search for novel targets and mechanisms. The ability of MTB to sense and become accustomed to changes in the host is essential for survival and confers the basis of infection. A crucial condition that MTB must surmount is iron limitation, during the establishment of infection, since iron is required by both bacteria and humans. This study focuses on how iron deprivation affects drug susceptibilities of known anti-TB drugs in Mycobacterium smegmatis, a “surrogate of MTB.” We showed that iron deprivation leads to enhanced potency of most commonly used first line anti-TB drugs that could be reverted upon iron supplementation. We explored that membrane homeostasis is disrupted upon iron deprivation as revealed by enhanced membrane permeability and hypersensitivity to membrane perturbing agent leading to increased passive diffusion of drug and TEM images showing detectable differences in cell envelope thickness. Furthermore, iron seems to be indispensable to sustain genotoxic stress suggesting its possible role in DNA repair machinery. Taken together, we for the first time established a link between cellular iron and drug susceptibility of mycobacteria suggesting iron as novel determinant to combat MDR.

Dynamin-like proteins are essential for vesicle biogenesis in Mycobacterium tuberculosis

“…Our ultrastructural analysis of hypervesiculating Mtb cells suggested a close link between EV release and cell envelope alterations. Our microscopy observations that indicate loss of OM thickness in Fe-limited Mtb are consistent with previous analysis of the cell envelope of Fe deficient Mtb which showed reduced cell envelope lipids (16) and enhanced cell envelope permeability (16, 36) associated with downregulation of mmpL3 (17). MmmpL3 transports trehalose monomycolate across the plasma membrane for outer membrane assembly (37).…”

Fungal-derived xenobiotic exhibits antibacterial and antibiofilm activity against <i>Staphylococcus aureus </i>

“…Such membrane disruption effect was further corroborated by cells spotted with celldisrupting chaotropic agent SDS and PI uptake assay. In presence of SDS, FI3 made cells hyper-sensitive similar to the study reported by Pal et al (38) and 45% higher PI was taken up upon treatment of 0.5× MIC FI3 as compared to positive control.…”

Elucidating the Mechanism of Vanillin Induced Mycobacterial Membrane Disruption: Implications of Lipid Alteration

“…The efflux of EtBr was determined by using protocol described previously [2]. Briefly, approximately 1×10 6 cells were grown until exponential phase in the absence (control) and in presence of Van at its sub-inhibitory concentration (15μg/ml).…”

“…According to World Health Organization (WHO) report there were estimated 1.8 million population deaths with TB in 2015 out of which 0.4 million deaths are only from HIV associated with TB [1]. The current anti-TB drug regimens which are used for the treatment of TB having different mechanisms of action after long term exposure suffers from development of multi drug resistance tuberculosis (MDR-TB) [2]. Mycobacterium tuberculosis (MTB), the causative agent of TB, possesses unique cell wall architecture which aides MTB to resist against several anti-TB drugs.…”