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Weiss, D. S.

Publications and source records attributed to Weiss, D. S..

22 records · Page 2Linked to original sources

FtsN activates septal cell wall synthesis by forming a processive complex with the septum-specific peptidoglycan synthase in E. coli

The FtsN protein of Escherichia coli and other proteobacteria is an essential and highly conserved bitopic membrane protein that triggers the inward synthesis of septal peptidoglycan (sPG) during cell division. Previous work has shown that the activation of sPG synthesis by FtsN involves a series of interactions of FtsN with other divisome proteins and the cell wall. Precisely how FtsN achieves this role is unclear, but a recent study has shown that FtsN promotes the relocation of the essential sPG synthase FtsWI from an FtsZ-associated track (where FtsWI is inactive) to an sPG-track (where FtsWI engages in sPG synthesis). Whether FtsN works by displacing FtsWI from the Z-track or capturing/retaining FtsWI on the sPG-track is not known. Here we use single-molecule imaging and genetic manipulation to investigate the organization and dynamics of FtsN at the septum and how they are coupled to sPG synthesis activity. We found that FtsN exhibits a spatial organization and dynamics distinct from those of the FtsZ-ring. Single FtsN molecules move processively as a single population with a speed of [~] 9 nm s-1, similar to the speed of active FtsWI molecules on the sPG-track, but significantly different from the [~] 30 nm s-1 speed of inactive FtsWI molecules on the FtsZ-track. Furthermore, the processive movement of FtsN is independent of FtsZs treadmilling dynamics but driven exclusively by active sPG synthesis. Importantly, only the essential domain of FtsN, a three-helix bundle in the periplasm, is required to maintain the processive complex containing both FtsWI and FtsN on the sPG-track. We conclude that FtsN activates sPG synthesis by forming a processive synthesis complex with FtsWI exclusively on the sPG-track. These findings favor a model in which FtsN captures or retains FtsWI on the sPG-track rather than one in which FtsN actively displaces FtsWI from the Z-track.

microbiology↗

Analysis of beta-lactam heteroresistance in CRE suggests a stage in the spectrum of antibiotic resistance

Antibiotic resistance is a growing crisis that threatens many aspects of modern healthcare. Dogma is that resistance often develops due to acquisition of a resistance gene or mutation, and that when this occurs, all the cells in the bacterial population are phenotypically resistant which we term "homogenous resistance". In contrast, heteroresistance (HR) is a form of antibiotic resistance where only a subset of cells within a bacterial population are resistant to a given drug. These resistant cells can rapidly replicate in the presence of the antibiotic and cause treatment failures. If and how HR and homogenous resistance are related is unclear. Using carbapenem-resistant Enterobacterales (CRE), we show that HR to beta-lactams develops over years of antibiotic usage and that it is gradually supplanted by homogenous resistance. This suggests the possibility that HR may often develop before homogenous resistance and frequently be a stage in its progression, representing a major shift in our understanding of the evolution of antibiotic resistance.

microbiology↗

Combinations of antifungals to effectively kill drug-resistant Candida auris

Candida auris is an emerging, highly virulent fungal pathogen that is often resistant to multiple classes of antifungals. To overcome this resistance, we investigated the in vitro efficacy of antifungal combinations, finding that amphotericin B/micafungin resulted in drastically reduced survival (~5 logs) of all 10 isolates tested including 2 that were refractory to each individual drug. These findings suggest that combination therapy with micafungin/amphotericin B may have clinical utility against broadly resistant C. auris.

microbiology↗

A xylose-inducible expression system and a CRISPRi-plasmid for targeted knock-down of gene expression in Clostridioides difficile

Here we introduce plasmids for xylose-regulated expression and repression of genes in Clostridioides difficile. The xylose-inducible expression vector allows for ~100-fold induction of an mCherryOpt reporter gene. Induction is titratable and uniform from cell-to-cell. The gene repression plasmid is a CRISPR-interference (CRISPRi) system based on a nuclease-defective, codon-optimized allele of the Streptococcus pyogenes Cas9 protein (dCas9) that is targeted to a gene of interest by a constitutively-expressed single guide RNA (sgRNA). Expression of dCas9 is induced by xylose, allowing investigators to control the timing and extent of gene-silencing, as demonstrated here by dose-dependent repression of a chromosomal gene for a red fluorescent protein (maximum repression ~100-fold). To validate the utility of CRISPRi for deciphering gene function in C. difficile, we knocked-down expression of three genes involved in biogenesis of the cell envelope: the cell division gene ftsZ, the S-layer protein gene slpA and the peptidoglycan synthase gene pbp-0712. CRISPRi confirmed known or expected phenotypes associated with loss of FtsZ and SlpA, and revealed that the previously uncharacterized peptidoglycan synthase PBP-0712 is needed for proper elongation, cell division and protection against lysis.\n\nImportanceClostridioides difficile has become the leading cause of hospital-acquired diarrhea in developed countries. A better understanding of the basic biology of this devastating pathogen might lead to novel approaches for preventing or treating C. difficile infections. Here we introduce new plasmid vectors that allow for titratable induction (Pxyl) or knockdown (CRISPRi) of gene expression. The CRISPRi plasmid allows for easy depletion of target proteins in C. difficile. Besides bypassing the lengthy process of mutant construction, CRISPRi can be used to study the function of essential genes, which are particularly important targets for antibiotic development.

microbiology↗