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We evaluated cefiderocol activity against carbapenem-resistant Pseudomonas aeruginosa (CRPA) and carbapenem-resistant Acinetobacter baumannii (CRAB), characterized the &#x3b2;-lactamase gene profiles of cefiderocol-nonsusceptible CRPA by metallo-&#x3b2;-lactamase (MBL) subtype, and assessed cross-resistance with comparator agents. Cefiderocol minimum inhibitory concentrations (MICs) for 890 CRPA and 1,063 CRAB isolates from the 2024 Antimicrobial Testing Leadership and Surveillance (ATLAS) program were determined by broth microdilution using iron-depleted cation-adjusted Mueller-Hinton broth. Cefiderocol nonsusceptibility was defined as MIC &#x2265; 8 mg/L per CLSI (intermediate + resistant). DTRPA was defined as nonsusceptible to all anti-pseudomonal &#x3b2;-lactams and fluoroquinolones; DTRAB was defined as nonsusceptible to carbapenems, ampicillin-sulbactam, and fluoroquinolones, reflecting species-specific susceptibility panels. CRPA isolates underwent molecular screening for blaNDM, blaVIM, blaIMP, serine carbapenemase, and ESBL genes; genotype data were not available for A. baumannii. Cefiderocol susceptibility was 93.9% for CRPA and 88.5% for CRAB, respectively (nonsusceptibility 6.1% and 11.5%, respectively; OR = 2.01, P < 0.001); nonsusceptibility among DTRPA and DTRAB was 8.1% and 11.7%, respectively. Among 54 cefiderocol-nonsusceptible CRPA, 41 (76%) harbored no detectable carbapenemase gene. Nonsusceptibility among MBL-positive CRPA was exclusively attributable to blaNDM producers (27.7%, 13/47); blaVIM-positive (n = 68) and blaIMP-positive (n = 21) isolates were uniformly susceptible. Among cefiderocol-nonsusceptible CRPA, 98.1% were co-resistant to ceftazidime-avibactam and 96.3% to ceftolozane-tazobactam.

The emergence and spread of mobilized colistin resistance (mcr) genes threaten the efficacy of colistin, a last-resort antibiotic used in the management of multidrug-resistant Gram-negative bacteria (GNB). This study was aimed at (1) providing a bibliometric assessment of the mcr-related research landscape and (2) conducting phylogenetic and metadata analyses of all known mcr gene variants to elucidate their relatedness and global distribution by country of origin, sample type, and harboring bacterial diversity. Bibliometric analysis was conducted following the SPAR-4-SLR methodology, where mcr-related publications were retrieved from Scopus and analyzed using diverse packages in R software, Datawrapper, the VOSviewer tool, and Biblioshiny. Genomic analysis was conducted on 116 complete mcr gene sequences retrieved from the National Center for Biotechnology Information (NCBI). A neighbor-joining phylogenetic tree was constructed to infer evolutionary relationships, and the associated metadata of sequences were analyzed. A total of 3936 mcr-related publications met the inclusion criteria. Since the discovery of mcr in 2015, research output has grown consistently through 2024, reflecting an intense global scientific mobilization and the rapid prioritization of colistin resistance given its significant public health threat. About 54.15% of studies appeared in Top Q1-Q2 journals, notably Frontiers in Microbiology and Antimicrobial Agents and Chemotherapy. The most cited work was Liu et al. (2016), with 4445 citations. China and India led in publications and collaborations, while China dominated funding. Phylogenetic analysis revealed 10 mcr variants, each clustering together. Distance analysis showed that Escherichia coli was the likely origin of mcr-1-2 and mcr-5 variants, Aeromonas of mcr-3, Moraxella of mcr-6, Klebsiella pneumoniae of mcr-7, Raoultella ornithinolytica of mcr-8, and Enterobacter cloacae of mcr-10. However, mcr-4 and mcr-9 showed multiple origins with similar branch lengths for E. coli, Salmonella, and Enterobacter. The widespread occurrence of mcr-1-10 across diverse bacterial species underscores the urgent need for an integrated, One Health surveillance approach to monitor and mitigate colistin resistance spread globally.

Campylobacter jejuni is the most common bacterial cause of human gastroenteritis around the world. A stable, scalable, and standardized typing scheme is essential for epidemiological and antimicrobial resistance (AMR) surveillance for prevention and control of C. jejuni infections. We curated, assembled, and quality-filtered a C. jejuni global whole-genome sequencing (WGS) data set of 63,012 publicly available Illumina short-read genomes. A C. jejuni global cgMLST scheme with 1,161 core loci was developed using a representative subset of 2,587 genomes. We compared the HierCC clustering of the cgMLST profiles at every allelic distance, and identified nine epidemiologically meaningful levels to form a novel multilevel HierCC typing (MHT) scheme. AMR prediction was performed for the global data set using AbritAMR and integrated with the MHT scheme. The multilevel design provides flexible typing resolution for both short- and long-term epidemiological investigations and allows natural and genetically discrete clusters to be described consistently at both global and local scales. We showcased the utility of the scheme with the identification of country- and continent-specific clusters at HC264 to HC19 levels and differentiation of farm-animal-specific (specialist) from human infection (generalist) clusters at HC264 to HC55 levels. In the U.S. dataset from 2016 to 2022, a total of 276 antibiotic-resistant clusters were identified, with 22 resistant clusters increasing in frequency in recent years. An increased prevalence of C. jejuni carrying 50S_L22 mutations in the USA was observed from 2016 to 2022, suggesting continuing selection pressure from macrolide use in farm animals.

Hypermutation-driven evolution is a major contributor to antibiotic resistance in some bacterial pathogens, but its role in Klebsiella pneumoniae remains poorly defined. We analyzed 11 KPC-producing ST258 K. pneumoniae isolates collected serially over ~4 years from a host with persistent colonization and recurrent infections. After >3 years, isolates acquired ceftazidime-avibactam (CZA) resistance with restored carbapenem susceptibility, coinciding with emergence of a V76G substitution in MutH, a conserved endonuclease in the DNA mismatch repair pathway. Isolates carrying mutHV76G demonstrated sharp increases in within-host genetic diversification (69-179 versus 2-12 SNPs), and accumulated mutations across multiple resistance-associated loci, including blaKPC-3, ompK36, cirA, and envZ. Both clinical mutHV76G isolates and CRISPR-Cas9-engineered mutants (mutHV76G and mutH null mutant) exhibited hypermutator phenotypes and showed accelerated acquisition of resistance or reduced susceptibility to CZA, meropenem-vaborbactam (MVB), and cefiderocol. Using matched isogenic engineered strains, we confirmed that mutHV76G heightens the pace of resistance evolution in vitro, enhances plasmid uptake and transfer, and increases bacterial fitness during mouse infections. Resistance pathways that emerged in vivo paralleled those observed clinically, including blaKPC-3 variants under CZA pressure and ompK36 mutations under MVB exposure. The similarity of mutHV76G and mutH-null phenotypes indicates that the V76G substitution largely abolishes MutH function. These findings identify MutH-mediated hypermutation as an adaptive strategy in K. pneumoniae that accelerates resistance to multiple last-line antibiotics and promotes horizontal gene transfer without apparent fitness cost.IMPORTANCEAntibiotic-resistant Klebsiella pneumoniae is a major global health threat, and resistance to new "last-line" antibiotics is rising. In this study, we examined a rare collection of carbapenem-resistant K. pneumoniae isolates obtained over 4 years from a single host, giving us an opportunity to observe how the bacterium evolved over time. During this period, the bacteria acquired a single nucleotide change in a DNA damage repair gene mutH, which caused them to accumulate mutations far more rapidly than with wild-type mutH. Through extensive genomic and experimental work, we found that this single change produced a hypermutator strain capable of quickly developing resistance to several key antibiotics, including ceftazidime-avibactam and meropenem-vaborbactam, and also reduced susceptibility to cefiderocol. Using laboratory-engineered strains, animal infection models, and detailed genetic analyses, we confirmed that the mutH mutation accelerates resistance development and increases the bacterium's ability to acquire resistance plasmids. Importantly, the same types of mutations that appeared under laboratory conditions also emerged during infection. Our findings show how hypermutation can compromise even the newest antibiotics and highlight the need for surveillance of DNA repair defects in antibiotic-resistant K. pneumoniae.

Invasive fungal diseases (IFDs), including invasive aspergillosis (IA) and invasive mucormycosis (IM), occur primarily in immunocompromised and/or hospitalized patients and are associated with increased morbidity and mortality. Isavuconazole and posaconazole are triazole compounds approved for the treatment of IA/IM in adults and children, while voriconazole is approved for IA treatment only. All triazole compounds inhibit CYP3A, and both isavuconazole and posaconazole inhibit the transporter P-gp. Pediatric patients being treated for leukemia with vincristine frequently experience fungal infections, requiring treatment. Vincristine is metabolized by CYP3A4 and CYP3A5 and eliminated via P-gp transport. The risk of drug-drug interactions (DDIs) between vincristine and triazole compounds is known; however, the magnitude of risk has not been quantified. In the present analysis, physiologically based pharmacokinetic (PBPK) models were built for the triazoles and vincristine in a pediatric cancer population using the Simcyp simulator and were used to predict the change in vincristine exposure following coadministration with triazoles. Different age groups and CYP3A5 phenotypes were also explored. Modeling predicted that vincristine geometric mean AUCinf ratios in CYP3A5 poor metabolizers (PMs) ranged from 2.01- to 2.25-fold, 4.97- to 5.20-fold, and 1.43- to 1.53-fold with isavuconazole, posaconazole, and voriconazole, respectively. In CYP3A5 extensive metabolizers (EMs), vincristine AUCinf ratios ranged from 1.22- to 1.38-fold, 1.19- to 1.24-fold, and 1.05- to 1.07-fold for isavuconazole, posaconazole, and voriconazole, respectively. The model predicted vincristine AUCinf >100 ng&#xb7;h/mL in CYP3A5 PM and <100 ng&#xb7;h/mL in CYP3A5 EM; therefore, vincristine dose reduction may be required only in CYP3A5 null expressors.

Invasive fungal infections (IFIs) remain a major global health threat due to limited therapeutic options and rising azole resistance. NT-a9 is a novel triazole antifungal with potent activity against Candida and Cryptococcus species via strong inhibition of ergosterol biosynthesis. In vitro, NT-a9 exhibited potent and sustained antifungal activity against clinical isolates, with superior potency compared to fluconazole (FLC). It also displayed a prolonged post-antifungal effect (PAFE) against most Candida species, a property rarely seen in conventional azoles. Resistance profiling demonstrated that NT-a9 possesses a high genetic barrier, fully suppressing resistant mutant emergence in Cryptococcus species and maintaining stable susceptibility in Candida albicans during 28 days of continuous exposure. NT-a9 retained potent activity against FLC-resistant Cryptococcus neoformans and multidrug-resistant Candida auris, with minimal influence from drug efflux mechanisms. In murine invasive candidiasis, a single low dose of NT-a9 achieved 100% survival and markedly reduced renal fungal burden, significantly outperforming FLC. NT-a9 also substantially improved survival in mice infected with FLC-resistant C. auris. Mechanistically, NT-a9 binds Erg11 with much higher affinity than FLC by forming key hydrogen bonds with Gly307 and His377, leading to irreversible ergosterol depletion, toxic sterol accumulation, and severe fungal membrane damage. Transcriptomic analysis further confirmed that NT-a9 extensively disrupts sterol biosynthesis and triggers compensatory gene expression that reinforces its antifungal action. As a novel triazole integrating long-lasting efficacy, a high resistance barrier, and potent activity against pan-azole-resistant pathogens, NT-a9 represents a promising clinical candidate for treating IFIs.

Cefiderocol (FDC) is a new siderophore-conjugated cephalosporin that enters the periplasm via iron transport systems. However, the specific contribution of individual iron uptake pathways to FDC activity remains unclear. We investigated the role of 13 iron acquisition systems using several Escherichia coli strain collections. FDC MICs were determined in iron-depleted and iron-supplemented media for E. coli mutants (Keio and pathogenic island [PAI]-deleted collections) and for no-acquired &#x3b2;-lactamase or TEM (NoBL/TEM-Ec) and NDM-producing E. coli (NDM-Ec) clinical isolates. Prevalence of iron uptake genes was assessed in these isolates, and fec operon prevalence and genomic location were investigated in E. coli genomes from EnteroBase and RefSeq databases. Compared to K-12 and 536 reference E. coli, only &#x394;cirA and &#x394;fiu (enterobactin system) showed increased FDC MICs (8- and 3-fold, respectively), while &#x394;fecA and &#x394;fecB had lower MICs (3-fold decrease). The fec operon, a known extraintestinal virulence factor, was significantly more prevalent in isolates with FDC MICs above median than below (96% vs. 33% in NoBL/TEM-Ec; 100% vs. 0% in NDM-Ec). According to EUCAST breakpoints, 63.6% of fec-positive NDM-Ec were resistant to FDC, whereas none of the fec-negative were. The fec operon was found in 46.5% of E. coli genomes, including virulent clones (ST131, 77%) and was mostly chromosome-borne (99%). Plasmid-borne fec closely resembled that of Enterobacter hormaechei or Klebsiella pneumoniae, suggesting interspecies transfer. Our findings highlight the role of Fec in reducing FDC susceptibility and promoting resistance in NDM-producing E. coli. They challenge the virulence-resistance trade-off demonstrating the "liaisons dangereuses" between iron and antibiotics.

This study was conducted to determine the potential effect of other antimicrobial agents on the in vitro activity of gepotidacin against six WHO N. gonorrhoeae and QC strain ATCC 49226 by checkerboard assays using Graver-Wade broth. Synergy and antagonism were evaluated using fractional inhibitory concentration (FIC) and FIC index (FICI) results for gepotidacin and comparator agents (azithromycin, cefixime, ceftriaxone, gemifloxacin, sitafloxacin, gentamicin, spectinomycin, doxycycline, and lefamulin). The evaluation of FICI showed no antagonistic or synergistic interactions, while the evaluation of individual FIC values revealed strain- and agent-specific synergistic or additive effects.

Safe and effective treatment options for tuberculosis (TB) are urgently needed for pregnant and lactating women due to the adverse maternal and neonatal outcomes associated with TB disease. Pretomanid is recommended by the World Health Organization for treatment of multidrug-resistant pulmonary TB in combination with bedaquiline and linezolid. However, this regimen is not recommended during pregnancy or breastfeeding due to the absence of clinical safety and efficacy data of pretomanid in these populations. This manuscript presents the nonclinical developmental and reproductive toxicology profile of pretomanid and clinical outcomes of pregnancies in women known to have been exposed to pretomanid. In nonclinical studies, pretomanid did not have a direct effect on fertility and reproductive function in female rats, and no adverse maternal or developmental effects were seen in rats or rabbits up to two times the clinical exposure during organogenesis. Additionally, no adverse developmental effects were observed in pups of pregnant rats orally dosed throughout gestation and lactation at approximately 1.5-fold clinical exposure. In the rat pre- and postnatal development study at 4.4-fold clinical exposure, there was maternal toxicity, lower pup body weights, and a delay in attaining the righting reflex, but no effects on fertility were seen in the male or female rat offspring. Clinically, 11 women became pregnant during pretomanid treatment: 5 had healthy babies, 5 had elective abortions, and 1 had a spontaneous abortion. The weight of evidence from preclinical studies and limited clinical outcomes supports further evaluation of pretomanid use in pregnant or lactating women.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT03086486.

Serratia species are Gram-negative pathogens responsible for a wide range of nosocomial infections. This multicenter nationwide retrospective study aimed to describe the epidemiology, clinical characteristics, antimicrobial susceptibility, and outcomes of Serratia infections in pediatric oncology patients and hematopoietic stem cell transplantation (HSCT) recipients in Poland between 2012 and 2023. A total of 36 Serratia infection episodes were identified in patients under 20 years of age, including 30 cases (83.3%) in the oncological (OHD) group and six (16.7%) among HSCT recipients. The median age was 4.30 years. The most common underlying diseases were acute lymphoblastic leukemia (36.1%) and central nervous system tumors (16.7%). Bloodstream infections predominated in OHD patients (33.3%), whereas urinary tract infections were most frequent in HSCT recipients (83.3%). S. marcescens was the most commonly isolated species. More than half of isolates (53.3%) showed antimicrobial resistance, with extended-spectrum &#x3b2;-lactamase (ESBL)-producing strains in 26.7% and AmpC &#x3b2;-lactamase-producing strains in 13.3%. Multidrug resistance occurred in 30%. Treatment most often included amikacin, piperacillin/tazobactam, and carbapenems. Five deaths occurred in the OHD group and one in the HSCT group, none directly related to Serratia infection. Although uncommon, Serratia infections remain clinically relevant due to their high antimicrobial resistance, underscoring the need for antimicrobial stewardship.

TBAJ-587 is a second-generation diarylquinoline with greater antimycobacterial activity and a potentially better safety profile than the first-generation bedaquiline. It is currently under development for the treatment of drug-susceptible and drug-resistant tuberculosis. A first-in-human trial of TBAJ-587, including single and multiple ascending oral doses and a dedicated food-effect cohort, was conducted in 92 healthy adults. Plasma exposures of TBAJ-587 were generally linear for AUCtau and slightly subproportional for Cmax, with the major circulating active metabolite, M3, remaining low relative to the parent. A high-fat meal increased the mean Cmax and AUClast 3.46- and 2.26-fold, respectively. TBAJ-587 accumulated with multiple dosing over the 28-day period, with mean accumulation ratios across the three tested doses ranging from 1.69 to 2.32 for Cmax and from 2.74 to 3.73 for AUCtau. However, steady-state conditions were not yet reached on day 28. Mean terminal half-lives after 28-day dosing of TBAJ-587 ranged from approximately 80 to 111 days. There were no deaths or serious adverse events, and TBAJ-587 was generally safe and well tolerated at single doses of 25-800 mg under fasting conditions and multiple doses of 50-200 mg once daily for 28 days after a standard breakfast. In addition, no dose- or time-dependent effects were noted for any of the other safety and tolerability parameters, including no clinically significant effects on the QTc interval. These results support further investigation of TBAJ-587 for the treatment of tuberculosis.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04890535.

Isavuconazole is approved for invasive aspergillosis (IA) and mucormycosis, but real-world data in patients with hematological malignancies are limited. This retrospective study (2022-2025) included adult patients with hematological malignancies and proven/probable invasive mold disease (IMD) who were treated with isavuconazole for &#x2265;72 h at two Chinese hospitals. The primary endpoint was week 6 treatment success (survival, clinical/radiological improvement, and no discontinuation due to failure/toxicity). Secondary endpoints included all-cause and IMD-attributable mortality at weeks 6 and 12 (competing risk analysis). Among 84 patients, 62 had aspergillosis (69.4% treatment success), 14 had mucormycosis (35.7%), and 8 had mixed infection (25.0%); the overall week 6 treatment success was 59.5% (50/84), with significant variation across infection types (P = 0.007) and treatment strategy (monotherapy 65.6% vs. combination 43.5%; P < 0.001), but not by therapy role. Week 6 all-cause and IMD-attributable mortality rates were 17.9% and 11.9%, respectively; IMD-attributable mortality rate was lower with monotherapy (6.6%) than with combination therapy (26.1%; P = 0.023). Week 12 all-cause mortality rate was 21.6%. Competing risk analysis showed significant differences in week 12 attributable mortality by infection type (overall P = 0.04): aspergillosis, 9.7%; mucormycosis, 36.0%; and mixed, 13.0%. Monotherapy was associated with lower attributable mortality than combination therapy (8.2% vs. 31.0%; P = 0.01). Four patients (4.8%) had drug-related adverse events (one discontinuation due to vomiting). In this real-world Chinese cohort, isavuconazole achieved 59.5% treatment success with favorable safety. Infection type and treatment strategy were key prognostic factors: aspergillosis and monotherapy were associated with better outcomes, whereas mucormycosis and combination therapy were associated with higher attributable mortality risk.

SARS-CoV-2 has undergone rapid genetic evolution, leading to the emergence of new variants with distinct mutations impacting global public health. Upon infection, the virus triggers a robust inflammatory response characterized by the release of pro-inflammatory cytokines, which play a central role in lung injury. It also alters the host antioxidant response, causing oxidative stress that supports viral replication and cytokine overproduction. This study investigated key pathogenic effectors in Calu-3 and A549-ACE2/TMPRSS2 cells infected with SARS-CoV-2 variants, focusing on replication kinetics, cellular redox state, and inflammatory cytokine profile. A dramatic redox alteration in terms of glutathione (GSH) and Cysteine (Cys) was observed at 48 h p.i., along with a strong pro-inflammatory cytokine response , likely via activation of the JNK/AP-1 signaling pathway. To counteract these effects, two thiol molecules were tested: I-152, a monothiol conjugate of N-Acetyl-Cysteine (NAC) and &#x3b2;-mercaptoethylamine (MEA) and its dithiol derivative, I-152SdAc. Thiols restored GSH balance by enhancing the expression of Nrf2-mediated genes, such as glutamate-Cys ligase modifier subunit (GCLM), and counteracted AP-1-mediated pathway, resulting in a significant reduction of inflammation and viral replication. Antiviral and anti-inflammatory activities of thiols were confirmed in NHBE cells. These findings highlight that redox imbalance is a key pathogenetic event in SARS-CoV-2 infection. Notably, besides Nrf2 and AP-1, other redox-sensitive factors, such as the CHAC glutathione-specific gamma-glutamyl-cyclotransferase 1 (CHAC1), seem to contribute to the pathogenesis and may represent a new potential therapeutic target of redox active compounds. Therefore, the thiol-derived molecules act as broadly effective compounds by limiting virus replication and inflammation.

Phage therapy and phage-antibiotic combinations are promising strategies against multidrug-resistant pathogens like carbapenem-resistant Klebsiella pneumoniae (CRKP). However, the mechanisms underlying phage resistance and the molecular basis of the rational design of phage-antibiotic combinations require further investigation. Using genome-wide transposon screening, CRISPR-Cas9 knockout, and plasmid complementation in a clinical ST11-KL64 CRKP strain, we investigated susceptibility determinants for phage P545 and their impact on antibiotic susceptibility. We identified multiple phage resistance mechanisms, including disruption of phage receptor lipopolysaccharide (LPS) biosynthesis genes (involving deletions of waaQ, wabH, wabG, ugd, galU, and wcaG), inhibition of phage burst through an undefined pathway (involving deletion of sirB1), and increased mutation frequency (involving deletions of mutS and mutL). Furthermore, we found that deletions of LPS-related genes reduced resistance to multiple antibiotics, while mutS and mutL deletions increased resistance to several antibiotics. Further synergy assays showed that P545 in combination with meropenem, colistin, or ceftazidime had synergistic effects in the in vitro killing of host bacteria. By integrating genetic screening and functional validation, our approach offers a versatile platform for dissecting phage targets, understanding resistance mechanisms, and evaluating phage-antibiotic interactions. These findings provide valuable tools and insights for optimizing phage-phage and phage-antibiotic combination therapies against clinically significant multidrug-resistant pathogens.

Imipenem/relebactam is a promising therapy for complicated intra-abdominal infections caused by carbapenem-resistant Enterobacterales species. However, data on tissue-site pharmacokinetics are limited. We evaluated the peritoneal penetration of imipenem and relebactam in healthy and infected rats by using microdialysis. The animals received a single intravenous infusion of imipenem (45 mg/kg) and relebactam (22.5 mg/kg), and unbound concentrations were dynamically monitored in the plasma and peritoneal fluid. Imipenem exposure in the peritoneal fluid was consistently lower than that in the plasma, with peritoneal fluid-to-plasma AUC ratios of 0.29 in the control group and 0.27 in the infection group. In contrast, relebactam demonstrated nearly equivalent concentrations in both compartments, with ratios of 0.81 and 0.86, respectively. Both agents reached peak levels at 30 min, and the semi-logarithmic curves showed rapid equilibrium without delay. The partition coefficients estimated by two-compartment modeling for imipenem (0.333-0.342) and relebactam (0.679-0.816) were consistent with non-compartmental results. Infection increased the distribution volume and clearance of relebactam but did not significantly alter peritoneal permeability for either drug. These findings provide the first description of the penetration of relebactam into peritoneal fluid. Subsequent pharmacodynamic target attainment (PTA) analysis showed that under the latest EUCAST PK/PD criteria, PTA values dropped markedly to an MIC of 1 mg/L, indicating a substantially reduced probability of achieving adequate peritoneal exposure. These results highlight the need for dosing strategies to ensure sufficient peritoneal drug concentration to maintain antimicrobial efficacy.

In this study, we evaluated the in silico and in vitro anticancer activity of the antimicrobial peptide epinecidin-1 (Epi-1) and its lysine-substituted variants (Variant-1 (Var-1) & Variant-2 (Var-2)). Computational docking demonstrated energetically favourable and structurally consistent interactions between the peptides and cancer-associated receptors (MerTK (PDB ID: 7OLX), EphA3 (PDB ID: 2QO9), TGF-&#x3b2; receptor I/ ALK5 (PDB ID: 3TZM), TrkA / NTRK1 (PDB ID: 4AOJ), and progesterone receptor (PDB ID: 1A28)), with distinct binding orientations and interaction profiles observed across the variants. Molecular dynamics simulation further substantiated these findings by confirming the stability of the selected receptor-ligand complex, with consistent root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA), and intermolecular hydrogen-bond interactions profiles indicating sustained interaction integrity under dynamic conditions. The in vitro antiproliferative activity of Epi-1 and its variants was assessed by MTT assays against A549, HeLa, HepG2, IMR-32 and MCF-7 cell lines. Both variants exhibited a two- to four-fold increase in cytotoxic activity compared with native Epi-1. We also evaluated the combinational activity of each peptide with doxorubicin, where peptide-doxorubicin treatments resulted in effective cancer cell killing at reduced drug concentrations relative to individual treatments, the Var-2&#x2009;+&#x2009;doxorubicin combination reduced cancer cell survival to below 10% at a combined concentration of 1&#xa0;&#xb5;g/mL (0.5&#xa0;&#xb5;g/mL peptide&#x2009;+&#x2009;0.5&#xa0;&#xb5;g/mL doxorubicin), compared with ~&#x2009;30% survival in doxorubicin alone. This has been added alongside the existing two- to four-fold cytotoxicity enhancement of the variants over wild-type Epi-1, to better convey the impact of the synergistic response. While inducing selective lysis in cancer cells, the peptides exhibited minimal cytotoxicity toward non-cancerous HEK 293 cells, indicating improved therapeutic selectivity. DCFH-DA staining confirmed intracellular reactive oxygen species generation, and Acridine Orange/Ethidium Bromide (AO/EtBr) staining demonstrated apoptosis as the predominant mode of cell death across the cancer cell lines, although Var-1 induced necrotic death in HepG2 cells.

Bacillus anthracis is a gram-positive, spore-forming bacterium and the etiological agent of anthrax. As a Tier 1 Select Agent, the pathogen can be isolated from the natural environment, and the endospore is a significant biological threat that can be produced in large quantities, stored, and disseminated by aerosolization. The intentional release of B. anthracis spores has the potential for mass casualties and is a serious threat to public and military health. Fluoroquinolones and tetracyclines are common antibiotics used for post-exposure prophylaxis and treatment in the United States (U.S.), whereas penicillin is the drug of choice throughout the rest of the world. However, these commonly used antibiotics may be contraindicated or suboptimal in a public health crisis. Thus, there is a need for novel medical countermeasures to be developed and tested against B. anthracis. Sulopenem is a broad-spectrum, orally bioavailable penem antibiotic recently approved in the U.S. for the treatment of uncomplicated urinary tract infections in women with limited therapeutic options. Here, we demonstrate that sulopenem has potent in vitro activity against both wild-type virulent B. anthracis strains, as well as biosafety level 2 surrogate strains resistant to current standards of care. Using human-equivalent dosing regimens, we show that sulopenem is highly protective in both the mouse and rabbit inhalational anthrax models. Together, these results support continued evaluation of this oral penem as a countermeasure for inhalational anthrax.

Secondary iliopsoas abscess arising from colorectal cancer is uncommon and diagnostically challenging. We report a woman in her 50s with locally recurrent sigmoid colon cancer who developed a massive gas-forming left iliopsoas abscess during capecitabine, oxaliplatin and bevacizumab. The acute presentation was severe, with altered consciousness reported before ambulance transfer, marked inflammatory response and need for urgent CT-guided drainage and intensive monitoring. Previous Escherichia coli bacteraemia, bilateral ureteral stents, polymicrobial anaerobic abscess flora and bevacizumab exposure created several plausible infection mechanisms. Abscess culture supported an enteric source whereas urine culture yielded discordant organisms. She improved after source control, broad-spectrum antimicrobial therapy with subsequent de-escalation and prolonged drainage, and was discharged after resuming systemic therapy without bevacizumab. This case emphasises early CT, multidisciplinary decision-making and cautious attribution of causality in oncology patients with flank pain and systemic inflammation.

Cytochrome P450 isotype 2D6 (CYP2D6) enzyme metabolizes the 8-aminoquinoline primaquine into its active form, 5-hydroxyprimaquine. Highly polymorphic CYP2D6 produces different enzyme activity levels among individuals. This diversity influences the therapeutic efficacy of primaquine in preventing Plasmodium vivax malaria relapses. Urinary 5,6-orthoquinone primaquine concentrations in Indonesian patients treated with primaquine for malaria were analyzed in relation to CYP2D6 genotype-predicted phenotypes and blood methemoglobin levels. We genotyped samples from 48 patients and classified them into three CYP2D6 metabolic activity groups: intermediate, normal, and ultra-rapid metabolizers. Methemoglobin levels were measured repeatedly up to 27 times over 72 h, including one pre-dose measurement and eight post-dose measurements per day at approximately 30-min intervals following primaquine administration. Intermediate metabolizers exhibited significantly lower urinary concentrations of 5,6-orthoquinone primaquine compared to normal and ultra-rapid metabolizers (geometric mean ratio: 2.24, 95% CI: 1.26-3.98, P = 0.01), indicative of reduced drug bioactivation. Methemoglobin concentrations gradually increased from Day 0 to Day 2, particularly in normal metabolizers. Day 2 methemoglobin levels were higher in normal/ultra-rapid metabolizers in our study sample (geometric mean ratio = 1.51; 95% CI: 0.84-2.70; P = 0.15). There was a strong positive relationship between urinary 5,6-orthoquinone primaquine and Day 2 methemoglobin levels (geometric mean ratio per 1,000 ng/mL increase = 1.90; 95% CI: 1.37-2.63; P = 0.0007). Our findings accord with the hypothesized utility of urinary 5,6-orthoquinone primaquine concentrations and methemoglobin levels as pharmacodynamic markers of primaquine bioactivation. Understanding and measuring the impacts of CYP2D6 polymorphisms will aid in interpreting clinical trials and optimizing primaquine dosing strategies.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT03916003.