Glutamate-gated chloride channel receptors and mechanisms of drug resistance in pathogenic species

Pulmonary infections are the most common clinical manifestations of Nocardia species. There is an increase in cases of nocardial infections occurring worldwide attributable to the increase in the immunosuppressed population. The availability of molecular methods has aided the detection of more number of cases as well as unusual species. Still, it remains one of the most underdiagnosed pathogens. Recognition of drug resistance in this organism has now mandated early and precise identification with speciation for effective treatment and management. Nocardial species identity can predict antimicrobial susceptibility and guide clinical management. Here, we report two cases of pulmonary nocardiosis caused by unusual species of Nocardia, namely, N. cyriacigeorgica and N. beijingensis identified by 16S rRNA gene-based sequencing. These cases are being reported for their rarity.

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Structure and efflux mechanism of the yeast pleiotropic drug resistance transporter Pdr5

10.1101/2021.02.09.430491 ◽

2021 ◽

Author(s):

Andrzej Harris ◽

Manuel Wagner ◽

Dijun Du ◽

Stefanie Raschka ◽

Holger Gohlke ◽

...

Keyword(s):

Drug Resistance ◽

Antifungal Agents ◽

Functional Results ◽

Drug Efflux ◽

Antifungal Compounds ◽

Pathogenic Species ◽

Peristaltic Motion ◽

Pleiotropic Drug Resistance ◽

Nucleotide Hydrolysis ◽

Efflux Mechanism

AbstractPdr5, a member of the extensive ABC transporter superfamily, is representative of a clinically relevant subgroup involved in pleiotropic drug resistance. Through the coupling of nucleotide hydrolysis with drug efflux, Pdr5 homologues enable pathogenic species to survive in the presence of chemically diverse antifungal agents. Our structural and functional results reveal details of an ATP-driven conformational cycle, which mechanically drives drug translocation through an amphipathic channel, and a clamping switch within a conserved linker loop that acts as a nucleotide sensor. One half of the transporter remains nearly invariant throughout the cycle, while its partner undergoes changes that are transmitted across interdomain interfaces to support a peristaltic motion of the pumped molecule. The efflux model proposed here rationalises the pleiotropic impact of Pdr5 and opens avenues for the development of effective antifungal compounds.

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The Role of Chloride Channels in the Multidrug Resistance

Membranes ◽

10.3390/membranes12010038 ◽

2021 ◽

Vol 12 (1) ◽

pp. 38

Author(s):

Bartosz Wilczyński ◽

Alicja Dąbrowska ◽

Jolanta Saczko ◽

Julita Kulbacka

Keyword(s):

Drug Resistance ◽

Multidrug Resistance ◽

Ion Channels ◽

Chloride Channel ◽

Chloride Channels ◽

Cell Metabolism ◽

A Subunit ◽

Cancerous Cells ◽

Volume Decrease

Nowadays, one of medicine’s main and most challenging aims is finding effective ways to treat cancer. Unfortunately, although there are numerous anti-cancerous drugs, such as cisplatin, more and more cancerous cells create drug resistance. Thus, it is equally important to find new medicines and research the drug resistance phenomenon and possibilities to avoid this mechanism. Ion channels, including chloride channels, play an important role in the drug resistance phenomenon. Our article focuses on the chloride channels, especially the volume-regulated channels (VRAC) and CLC chloride channels family. VRAC induces multidrug resistance (MDR) by causing apoptosis connected with apoptotic volume decrease (AVD) and VRAC are responsible for the transport of anti-cancerous drugs such as cisplatin. VRACs are a group of heterogenic complexes made from leucine-rich repetition with 8A (LRRC8A) and a subunit LRRC8B-E responsible for the properties. There are probably other subunits, which can create those channels, for example, TTYH1 and TTYH2. It is also known that the ClC family is involved in creating MDR in mainly two mechanisms—by changing the cell metabolism or acidification of the cell. The most researched chloride channel from this family is the CLC-3 channel. However, other channels are playing an important role in inducing MDR as well. In this paper, we review the role of chloride channels in MDR and establish the role of the channels in the MDR phenomenon.

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