Complement-resistance mechanisms of bacteria

Apropos to the article by Dr Bali, titled “Mupirocin resistance in clinical isolates of methicillin-sensitive and resistant Staphylococcus aureus in a tertiary care centre of North India” (1), the authors have raised important issue of emerging antimicrobial resistance (AMR). Antimicrobial resistance is an increasingly serious threat to global public health that requires action across all government sectors and society. As per WHO, AMR lurks the effective prevention and management of an ever-increasing spectrum of infections caused by bacteria, parasites, fungi and viruses. Novel resistance mechanisms are emerging and spreading globally, threatening the man’s ability to treat common infectious diseases.

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Evaluation of Potent Isoquinoline-Based Thiosemicarbazone Antiproliferatives Against Solid Tumor Models

10.26434/chemrxiv.7877987.v1 ◽

2019 ◽

Author(s):

Daniel Sun ◽

Soumya Poddar ◽

Roy D. Pan ◽

Juno Van Valkenburgh ◽

Ethan Rosser ◽

...

Keyword(s):

Solid Tumor ◽

Small Cell Lung Carcinoma ◽

Single Agent ◽

Resistance Mechanisms ◽

Tumor Models ◽

Cell Lung Carcinoma ◽

Adaptive Resistance ◽

Cancer Models ◽

Nanomolar Range

The lead compound, an ⍺-N-heterocyclic carboxaldehyde thiosemicarbazone HCT-13, was highly potent against a panel of pancreatic, small cell lung carcinoma, and prostate cancer models, with IC90 values in the low-to-mid nanomolar range. We show that the cytotoxicity of HCT-13 is copper-dependent, that it acts as a copper ionophore, induces production of reactive oxygen species (ROS), and promotes mitochondrial dysfunction and S-phase arrest. Lastly, DNA damage response/replication stress response (DDR/RSR) pathways, specifically Ataxia-Telangiectasia Mutated (ATM) and Rad3-related protein kinase (ATR), were identified as actionable adaptive resistance mechanisms following HCT-13 treatment. Taken together, HCT-13 is potent against solid tumor models and warrants in vivo evaluation against aggressive tumor models, either as a single agent or as part of a combination therapy.

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5-Benzylidene-4-Oxazolidinones are Synergistic with Antibiotics for the Treatment of Staphylococcus Aureus Biofilms

10.26434/chemrxiv.9759302.v1 ◽

2019 ◽

Author(s):

Bram Frohock ◽

Jessica M. Gilbertie ◽

Jennifer C. Daiker ◽

Lauren V. Schnabel ◽

Joshua Pierce

Keyword(s):

Staphylococcus Aureus ◽

Human Health ◽

Matrix Model ◽

Bacterial Load ◽

Collagen Matrix ◽

Resistance Mechanisms ◽

Novel Therapeutics ◽

Innovative Treatment ◽

Antibiotic Action ◽

Biofilm Infection

<div>The failure of frontline antibiotics in the clinic is one of the most serious threats to human health and requires a multitude of novel therapeutics and innovative treatment approaches to curtail the growing crisis. In addition to traditional resistance mechanisms resulting in the lack of efficacy of many antibiotics, most chronic and recurring infections are further made tolerant to antibiotic action by the presence of biofilms. Herein, we report an expanded set of 5-benzylidene-4-oxazolidinones that are able to inhibit the formation of Staphylococcus aureus biofilms, disperse preformed biofilms and in combination with common antibiotics are able to significantly reduce the bacterial load in a robust collagen-matrix model of biofilm infection.</div>

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