Nutrient Stress Small-Molecule Screening Platform for Escherichia coli

Abstract

Clinically approved antibiotics target a narrow spectrum of cellular processes, namely cell wall synthesis, DNA replication, and protein synthesis. Numerous screens have been designed to identify inhibitors that target one of these cellular processes. Indeed, this narrow range of drug mechanisms and a reliance on chemical classes discovered many decades ago are thought to be principally responsible for the current crisis of antibiotic drug resistance. Seeking to expand the target base of antibacterial drug discovery, we developed a nutrient stress screening platform that identifies inhibitors of the growth of in Escherichia coli under nutrient limitation. Under nutrient stress, bacteria require an expanded biosynthetic capacity that includes the synthesis of amino acids, vitamins, and nucleobases. Growing evidence suggests that these processes may be indispensable to certain pathogens and at particular sites of infection. Indeed, more than 100 biosynthetic enzymes become indispensable to E. coli grown under nutrient stress in vitro. The screening platform described here puts a focus on these novel targets for new antibiotics and prioritizes growth inhibitory compounds that can be suppressed by individual nutrients and pools thereof.

Functional Prediction of Biological Profile During Eutrophication in Marine Environment

“…These BPs and MPs involve biochemical reactions and pathways that ultimately lead to the formation of precursor metabolites and substances from which energy is derived. 39 - 44 This energy production is essential for the regulation of nutrient content during stress, to persist long enough, continue its cycle, and invade a new host. 45 …”

“…These BPs and MPs involve biochemical reactions and pathways that ultimately lead to the formation of precursor metabolites and substances from which energy is derived. [39][40][41][42][43][44] This energy production is essential for the regulation of nutrient content during stress, to persist long enough, continue its cycle, and invade a new host. 45 Simultaneously, the 10 genes chosen as hub proteins (Table 3) based on their combined score and their connectivity in Figure 2, which shows a co-expression profile, neighborhood, and appearance links between them and between (eno, ftsH, ravA, codA, hemN/yggW, puuD, codA, mngB, norV, can) that encoded for virulence factors such as ferrochatalases, metalloenzymes, enolases, hydrolases, and cytotoxic chemotherapeutic agents.…”

An Oral Fluorouracil Prodrug, Capecitabine, Mitigates a Gram-Positive Systemic Infection in Mice

“…Bacteria respond to nutritional restrictions by reprograming gene expression and activating diverse metabolic and catabolic pathways that enable virulence ( 12 – 14 ). Researchers have applied this information by screening for compounds that have antimicrobial activity in nutrient-poor media ( 15 , 16 ).…”