Covalent Inhibition of a Host-Pathogen Protein-Protein Interaction Reduces the Infectivity of Streptococcus pneumoniae.

The ever-expanding antibiotic resistance urgently calls for novel antibacterial therapeutics, especially those with a new mode of action. We report herein our exploration of protein-protein interaction (PPI) inhibition as a new mechanism to thwart bacterial pathogenesis. Specifically, we describe potent and specific inhibitors of the pneumococcal surface protein PspC, an important virulence factor that facilitates the infection of Streptococcus pneumoniae. Specifically, PspC has been documented to recruit human complement factor H (hFH) to suppress host complement activation and/or promote the bacterial attachment to host tissues. The CCP9 domain of hFH was recombinantly expressed to inhibit the PspC-hFH interaction as demonstrated on live pneumococcal cells. The inhibitor allowed for the first pharmacological intervention of the PspC-hFH interaction. This PPI inhibition reduced pneumococci's attachment to epithelial cells and also resensitized the D39 strain of S. pneumoniae for opsonization. Importantly, we have further devised covalent versions of CCP9, which afforded long-lasting PspC inhibition with low nanomolar potency. Overall, our results showcase the promise of PPI inhibition for combating bacterial infections as well as the power of covalent inhibitors.

The relationship between maternal exposure to ambient air pollutants and premature rupture of membranes: A systematic review and meta-analysis.

Air pollution is an environmental stimulus that may predispose pregnant women to preterm rapture of membrane (PROM). However, the relationship of maternal exposure to air pollutants and PROM is still unclear. To investigate the relationship between the long-term and short-term maternal exposure to air pollution and PROM. We searched all studies published in PubMed, Embase and Web of Science up to February 2024. The studies provided quantitative effect estimates with 95% confidence intervals, for the impact of short-term (<30 days) or long-term (≥30 days) maternal exposure to air pollutants on PROM, preterm PROM (PPROM) or term PROM (TPROM). The odds ratio (OR), risk ratio (RR), or hazard ratio (HR), with 95% confidence intervals was extracted, and RR or HR were deemed as OR because of the low prevalence of PROM. Fixed- or random-effects meta-analyses performed. In total, 17 relevant studies were included. Maternal exposure to PM2.5 in the second trimester increases the risk of PROM (pooled OR = 1.15, 95%CI: 1.05-1.26). Maternal exposure to PM10, NO2, NO, CO and SO2 during pregnancy and short-term maternal exposure to PM2.5, NO2, SO2 and O3 also associate with PROM occurrence. The results of the study show that both long-term maternal exposure in the second or third trimester and short-term maternal exposure to ambient air pollution can increase the risk of PROM.

Fluorosulfate as a Latent Sulfate in Peptides and Proteins.

Sulfation widely exists in the eukaryotic proteome. However, understanding the biological functions of sulfation in peptides and proteins has been hampered by the lack of methods to control its spatial or temporal distribution in the proteome. Herein, we report that fluorosulfate can serve as a latent precursor of sulfate in peptides and proteins, which can be efficiently converted to sulfate by hydroxamic acid reagents under physiologically relevant conditions. Photocaging the hydroxamic acid reagents further allowed for the light-controlled activation of functional sulfopeptides. This work provides a valuable tool for probing the functional roles of sulfation in peptides and proteins.

Lysine-Targeting Reversible Covalent Inhibitors with Long Residence Time.

We report a new reversible lysine conjugation that features a novel diazaborine product and much slowed dissociation kinetics in comparison to the previously known iminoboronate chemistry. Incorporating the diazaborine-forming warhead RMR1 to a peptide ligand gives potent and long-acting reversible covalent inhibitors of the staphylococcal sortase. The efficacy of sortase inhibition is demonstrated via biochemical and cell-based assays. A comparative study of RMR1 and an iminoboronate-forming warhead highlights the significance and potential of modulating bond dissociation kinetics in achieving long-acting reversible covalent inhibitors.

Different transmission routes and the risk of advanced HIV disease: A systematic review and network meta-analysis of observational studies.

BACKGROUND: A substantial proportion of people living with HIV (PLHIV) present for care with advanced HIV disease (AHD), which may result in difficulty reaching the "90-90-90" target to end AIDS in 2030. We assessed the risk of AHD for different transmission routes to summarize the evidence for priority prevention strategies for key populations. METHODS: Observational studies published before September 10th, 2019 in the PubMed, EMBASE, Web of Science and Chinese electronic databases were analysed. The outcomes of interest were the number of PLHIV and AHD patients and their associated transmission routes. We assessed the risk of AHD among the different transmission routes using the multi-armed network meta-analysis based on the Bayesian method. The associations between AHD and regional policies for sex work and compulsory drug treatment were estimated using ecological linear regression. FINDINGS: One hundred and one articles were included, covering 129,780 PLHIV with 478,830 patients who developed AHD. The network analysis revealed that among PLHIV, heterosexual contact was associated with the highest risk of AHD, followed by injection drug use (odds ratio [OR]=0•56, 95% credible interval [CrI] 0•47-0•68), and men who have sex with men (OR=0•54, 95% CrI 0•46-0•63). Regions that criminalized sex work and compulsory drug treatment had higher risks for AHD than those that did not. INTERPRETATION: Our findings suggest HC is at a higher risk of AHD compared to IDU and MSM. This justifies the need to expand prevention campaigns and maintain efforts to increase HIV testing in the heterosexual population.