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Light-activated molecular machines are new mode-of-action, fast-acting broad-spectrum antibacterials that target the membrane

ABSTRACT: Light-activated molecular machines are new mode-of-action, fast-acting broad-spectrum antibacterials that target the membrane

PROVIDER: PRJNA800066 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17720655_1.fastq.gz	Fastqsanger.gz
	SRR17720655_2.fastq.gz	Fastqsanger.gz
	SRR17720656_1.fastq.gz	Fastqsanger.gz
	SRR17720656_2.fastq.gz	Fastqsanger.gz
	SRR17720657_1.fastq.gz	Fastqsanger.gz

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Light-activated molecular machines are new mode-of-action, fast-acting broad-spectrum antibacterials that target the membrane

Project description:Light-activated molecular machines (MNM) are synthetic molecular structures that, following light activation, undergo successive unidirectional rotation that results in a drilling-like rapid motion that can thrust the motor through biological membranes.Visible light (405 nm) activated MM were investigated for their antibacterial potential and their mechanism of action was investigated by RNAseq.

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Project description:<p>Characterizing the mode of action of antimalarial compounds that emerge from high-throughput phenotypic screens is central to understanding how parasite resistance to these drugs can emerge. Here, we have employed untargeted metabolomics to inform on the mechanism of action of antimalarial leads with different speed of kill profiles being developed by the Novartis Institute of Tropical Diseases (NITD). Time-resolved global changes in malaria parasite metabolite profiles upon drug treatment were quantified using liquid chromatography-based mass spectrometry (LC-MS) and compared to untreated controls. Using this approach, we confirmed previously reported metabolomics profiles of the fast-killing (2.5 h) drug dihydroartemisinin (DHA) and the slower killing atovaquone (ATQ). A slow acting antimalarial lead from NITD of imidazolopiperazine (IZP) class, GNF179, elicited little or no discernable metabolic change in malaria parasites in the same 2.5 h window of drug exposure. In contrast, fast killing drugs, DHA and the spiroindolone (NITD246) elicited similar metabolomic profiles both in terms of kinetics and content. DHA and NITD246 induced peptide losses consistent with disruption of haemoglobin catabolism and also interfered with the pyrimidine biosynthesis pathway. Two members of the recently described novel class of antimalarial agents of the 5-aryl-2-amino-imidazothiadiazole (ITD) class also exhibited a fast-acting profile that also featured peptide losses indicative of disrupted haemoglobin catabolism. Our screen demonstrates that structurally unrelated, fast acting antimalarial compounds generate similar biochemical signatures in <em>Plasmodium</em> pointing to a common mechanism associated with rapid parasite death. These profiles may be used to identify and possibly predict the mode of action of other fast-acting drug candidates.</p>

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Light-activated molecular machines are fast-acting broad-spectrum antibacterials that target the membrane.

Project description:The increasing occurrence of antibiotic-resistant bacteria and the dwindling antibiotic research and development pipeline have created a pressing global health crisis. Here, we report the discovery of a distinctive antibacterial therapy that uses visible (405 nanometers) light-activated synthetic molecular machines (MMs) to kill Gram-negative and Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, in minutes, vastly outpacing conventional antibiotics. MMs also rapidly eliminate persister cells and established bacterial biofilms. The antibacterial mode of action of MMs involves physical disruption of the membrane. In addition, by permeabilizing the membrane, MMs at sublethal doses potentiate the action of conventional antibiotics. Repeated exposure to antibacterial MMs is not accompanied by resistance development. Finally, therapeutic doses of MMs mitigate mortality associated with bacterial infection in an in vivo model of burn wound infection. Visible light-activated MMs represent an unconventional antibacterial mode of action by mechanical disruption at the molecular scale, not existent in nature and to which resistance development is unlikely.

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Six homeoproteins and a linc-RNA cooperate at the fast MYH locus to lock terminal fast myofibre phenotype

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