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Rheumatic Heart Disease (RHD) persists as a major cardiovascular driver of mortality and morbidity among young people in low-and middle-income countries. Secondary antibiotic prophylaxis (SAP) with penicillin remains the cornerstone of RHD control, however, suboptimal treatment adherence undermines most secondary prevention programs. Many of the barriers to optimal SAP adherence are specific to the intramuscular form of penicillin and may potentially be overcome by use of oral penicillin. This noninferiority trial is comparing the efficacy of intramuscular to oral penicillin SAP to prevent progression of mild RHD at 2 years. The Intramuscular vs Enteral Penicillin Prophylaxis to Prevent Progression of Rheumatic Heart Disease (GOALIE) trial is randomizing Ugandan children aged 5 to 17 years identified by echocardiographic screening with mild RHD (Stage A or B as defined by 2023 World Heart Federation criteria) to Benzathine Benzyl Penicillin G (BPG arm, every-28-day intramuscular penicillin) or Phenoxymethyl Penicillin (Pen V arm, twice daily oral penicillin) for a period of 2 years. A blinded echocardiography adjudication panel of 3 RHD experts and 2 cardiologists is determining the echocardiographic stage of RHD at enrollment and will do the same at study completion by consensus review. Treatment adherence and study retention are supported through peer support groups and case management strategies. The primary outcome is the proportion of children in the Pen V arm who progress to more advanced RHD compared to those in the BPG arm. Secondary outcomes are patient-reported outcomes (treatment acceptance, satisfaction, and health related quality of life), costs, and cost-effectiveness of oral compared to intramuscular penicillin prophylaxis for RHD. A total sample size of 1,004 participants will provide 90% power to demonstrate noninferiority using a margin of 4% with allowance for 7% loss to follow-up. Participant enrollment commenced in October 2023 and final participant follow-up is expected in December 2026. The graphical abstract (Fig. 1) summarizes the flow of echocardiographic screening, participant enrollment and follow-up. The GOALIE trial is critical in global efforts to refine a pragmatic approach to secondary prevention for RHD control. GOALIE insists that the inferiority of oral penicillin be proven contemporarily and against the most important near-term clinical outcome of progression of RHD severity. This work also considers other factors that could influence the adoption of oral prophylaxis and change the calculus for acceptable efficacy including patient-reported outcomes and costs. ClinicalTrials.gov: NCT05693545

In a randomized trial of secondary antibiotic prophylaxis in Ugandan children and adolescents with latent rheumatic heart disease, penicillin G benzathine given every 4 weeks for 2 years reduced the risk of disease progression. Among 458 participants in the prophylaxis group, 2 had serious adverse events that were attributable to prophylaxis, including one episode of anaphylaxis.

Streptococcus pneumoniae ( S. pneumoniae ) has developed resistance to β-lactam antibiotics, largely due to mutations in penicillin-binding protein 2x (PBP2x), particularly within conserved motifs such as STMK and KSG. PBP2x mutations are frequently reported in multidrug-resistant pneumococcal strains associated with pneumonia, meningitis, and septicaemia. especially in serotypes 19A, 19F, and 23F, showing reduced susceptibility to β-lactam antibiotics. These mutations in the PBP2x disrupt antibiotic binding and enzymatic functions, highlighting the need for alternative therapeutic strategies. This study focused on five clinically relevant PBP2x mutations (T338A/G/P and K547G/T) within its active site. A library of phytocompounds was screened using a machine learning model trained to identify antibacterial compounds. Top candidates were filtered based on ADMET properties, and their electronic characteristics were assessed using HOMO–LUMO analysis and electrostatic potential mapping, through density functional theory (DFT). Glucozaluzanin C, a phytochemical derived from Elephantopus scaber , emerged as a potential candidate. Molecular docking and dynamics simulations revealed strong binding affinity and structural integrity with all PBP2x mutants, over a 100-ns timescale. RMSD, RMSF, and hydrogen bonding analysis confirmed stable interactions, suggesting Glucozaluzanin C may effectively interact with PBP2x mutants. Overall, the study highlights an effective strategy for identifying plant-derived inhibitors against β-lactam-resistant S. pneumoniae.

Infections caused by multidrug-resistant Streptococcus pneumoniae remain the leading cause of pneumonia-related deaths in children < 5 years globally, and mutations in penicillin-binding protein (PBP) 2 × have been identified as the major cause of resistance in the organism to beta-lactams. Thus, the development of new modulators with enhanced binding of PBP2x is highly encouraged. In this study, phenolics, due to their reported antibacterial activities, were screened against the active site of PBP2x using structure-based pharmacophore and molecular docking techniques, and the ability of the top-hit phenolics to inhibit the active and allosteric sites of PBP2x was refined through 120 ns molecular dynamic simulation. Except for gallocatechin gallate and lysidicichin, respectively, at the active and allosteric sites of PBP2x, the top-hit phenolics had higher negative binding free energy (ΔG bind ) than amoxicillin [active site (− 19.23 kcal/mol), allosteric site (− 33.75 kcal/mol)]. Although silicristin had the best broad-spectrum effects at the active (− 38.41 kcal/mol) and allosteric (− 50.54 kcal/mol) sites of PBP2x, the high thermodynamic entropy (4.90 Å) of the resulting complex might suggest the need for its possible structural refinement for enhanced potency. Interestingly, silicristin had a predicted synthetic feasibility score of < 5 and quantum calculations using the DFT B3LYP/6-31G+ (dp) revealed that silicristin is less stable and more reactive than amoxicillin. These findings point to the possible benefits of the top-hit phenolics, and most especially silicristin, in the direct and synergistic treatment of infections caused by S. pneumoniae . Accordingly, silicristin is currently the subject of further confirmatory in vitro research.

Stenotrophomonas maltophilia are opportunistic, multi-drug-resistant Gram-negative pathogens increasingly prevalent in clinical settings. Quorum sensing (QS) systems play a crucial role in their pathogenesis, coordinating bacterial populations and enabling interactions within polymicrobial communities. While not the primary QS mechanism in S. maltophilia , these bacteria can respond to acyl-homoserine lactone (AHL)-type autoinducers. Some isolates exhibit AHL-quorum quenching activity, though the responsible components remain unidentified. Homology searches in S. maltophilia K279a revealed a protein with the locus tag SMLT_RS07305 (old locus tag Smlt1522), annotated as a putative penicillin acylase 2 precursor. Sequence and structural analyses classify this protein within the bacterial AHL-acylase group B, characterized by a heterodimeric structure consisting of α- and β-subunits connected by a spacer polypeptide. We experimentally confirmed the dual activity of Smlt1522 as an AHL-acylase and a penicillin acylase. This protein degrades AHLs with varying acyl chains and hydrolyses penicillin antibiotics in vitro, in vivo, and as an heterologously expressed product. Its physiological role includes the modulation of beta-lactam resistance, biofilm formation and bacterial fitness under specific conditions. Evolutionary analysis suggests structural and functional conservation, pointing to its potential role in the adaptation of S. maltophilia to diverse and competitive environments.

Virulence pathways in gram-negative pathogenic bacteria are regulated by quorum sensing mechanisms, through the production and sensing of N- acylhomoserine lactone (AHL) signal molecules. Enzymatic degradation of AHLs leading to attenuation of virulence (quorum quenching) could pave the way for the development of new antibacterials. Penicillin V acylases (PVAs) belong to the Ntn hydrolase superfamily, together with AHL acylases. PVAs are exploited widely in the pharmaceutical industry, but their role in the natural physiology of their native microbes is not clearly understood. This report details the characterization of AHL degradation activity by homotetrameric PVAs from two gram-negative plant pathogenic bacteria, Pectobacterium atrosepticum ( Pa PVA) and Agrobacterium tumefaciens ( At PVA). Both the PVAs exhibited substrate specificity for degrading long-chain AHLs. Exogenous addition of these enzymes into Pseudomonas aeruginosa greatly diminished the production of elastase and pyocyanin and biofilm formation and increased the survival rate in an insect model of acute infection. Subtle structural differences in the PVA active site that regulate specificity for acyl chain length have been characterized, which could reflect the evolution of AHL-degrading acylases in relation to the environment of the bacteria that produce them and also provide strategies for enzyme engineering. The potential for using these enzymes as therapeutic agents in clinical applications and a few ideas about their possible significance in microbial physiology have also been discussed.

In this randomized, controlled trial, persons with early syphilis received a single treatment or three treatments with benzathine penicillin G at a dose of 2.4 million units. No benefit was seen with the additional doses.