Citrate serves as a signal molecule to modulate carbon metabolism and iron homeostasis in Staphylococcus aureus.

Pathogenic bacteria's metabolic adaptation for survival and proliferation within hosts is a crucial aspect of bacterial pathogenesis. Here, we demonstrate that citrate, the first intermediate of the tricarboxylic acid (TCA) cycle, plays a key role as a regulator of gene expression in Staphylococcus aureus. We show that citrate activates the transcriptional regulator CcpE and thus modulates the expression of numerous genes involved in key cellular pathways such as central carbon metabolism, iron uptake and the synthesis and export of virulence factors. Citrate can also suppress the transcriptional regulatory activity of ferric uptake regulator. Moreover, we determined that accumulated intracellular citrate, partly through the activation of CcpE, decreases the pathogenic potential of S. aureus in animal infection models. Therefore, citrate plays a pivotal role in coordinating carbon metabolism, iron homeostasis, and bacterial pathogenicity at the transcriptional level in S. aureus, going beyond its established role as a TCA cycle intermediate.

Enhancing oral delivery and anticancer efficacy of 7-ethyl-10-hydroxycamptothecin through self-assembled micelles of deoxycholic acid grafted N'-nonyl-trimethyl chitosan.

Irinotecan (CPT-11) is used as a first or second-line chemotherapy drug for the treatment and management of colorectal cancers. In vitro studies have shown that 7-ethyl-10-hydroxycamptothecin (SN38), the active metabolite of CPT-11, displays promising anticancer efficacy. However, its poor aqueous solubility and hydrolytic degradation result in its lower oral bioavailability and impracticable clinical application. To overcome these limitations, a novel amphiphilic chitosan derivative, deoxycholic acid decorated N'-nonyl-trimethyl chitosan, was synthesized. Nano-micelles loaded with SN38 were subsequently prepared to enhance the bioavailability and anti-tumor efficacy of the drug through oral administration. The nano-micelles demonstrated improved dilution stability, enhanced greater mucosal adherence, significant P-gp efflux inhibition, and increased drug transport in the intestine by paracellular and transcellular pathways. Consequently, both the in vivo pharmacokinetic profile and therapeutic efficacy of SN38 against cancer were substantially improved via the micellar system. Thus, the developed polymeric micelles can potentially enhance the SN38 oral absorption for cancer therapy, offering prospective avenues for further exploration.