Aspergillus fumigatus is responsible for a disproportionate number of invasive mycosis cases relative to other common filamentous fungi. While many fungal factors critical for infection establishment are known, genes essential for disease persistence and progression are ill defined. We propose that fungal factors that promote navigation of the rapidly changing nutrient and structural landscape characteristic of disease progression represent untapped clinically relevant therapeutic targets. To this end, we find that A. fumigatus requires a carbon catabolite repression (CCR) mediated genetic network to support in vivo fungal fitness and disease progression. While CCR as mediated by the transcriptional repressor CreA is not required for pulmonary infection establishment, loss of CCR inhibits fungal metabolic plasticity and the ability to thrive in the dynamic infection microenvironment. Our results suggest a model whereby CCR in an environmental filamentous fungus is dispensable for initiation of pulmonary infection but essential for infection maintenance and disease progression. Conceptually, we argue these data provide a foundation for additional studies on fungal factors required to support fungal fitness and disease progression and term such genes and factors, DPFs (disease progression factors). Medical treatment advances such as organ transplants and chemotherapies that suppress the immune system have increased the number of patients susceptible to invasive fungal diseases. The most common filamentous fungus isolated from these infections is the environmental mold, Aspergillus fumigatus, the causative agent of invasive aspergillosis (IA). Despite medical intervention, mortality from IA remains high, underscoring the need to understand A. fumigatus pathogenesis mechanisms to uncover new therapeutic targets and strategies. Here, we show that regulation of central metabolism in A. fumigatus is critical for infection maintenance and progression of disease. The dysregulation of carbon catabolite repression results in reduced virulence in an animal model at later stages of the infection because of an inability to navigate infection microenvironment dynamics driven in part by oxygen depletion and alterations in nutrient availability. These results likely not only apply to IA, but are broadly applicable to other infection models stressing the need to understand spatiotemporal dynamics of individual microbial infections particularly at the level of metabolism. We propose that microbial genes which support disease progression, in contrast but not mutually exclusive to disease initiation, be termed DPFs (disease progression factors) and as such represent a novel class of antimicrobial drug targets.

Alkyl quinolone has been proven to be a privileged scaffold in the antimicrobial drug discovery pipeline. In this study, a series of new 4-hydroxy-2-quinolinone analogs containing a long alkyl side chain at C-3 and a broad range of substituents on the C-6 and C-7 positions were synthesized. The antibacterial and antifungal activities of these analogs against Staphylococcus aureus, Escherichia coli, and Aspergillus flavus were investigated. The structure-activity relationship study revealed that the length of the alkyl chain, as well as the type of substituent, has a dramatic impact on the antimicrobial activities. Particularly, the brominated analogs 3j with a nonyl side chain exhibited exceptional antifungal activities against A. flavus (half maximal inhibitory concentration (IC₅₀) = 1.05 µg/mL), which surpassed that of the amphotericin B used as a positive control. The antibacterial activity against S. aureus, although not as potent, showed a similar trend to the antifungal activity. The data suggest that the 4-hydroxy-2-quinolone is a promising framework for the further development of new antimicrobial agents, especially for antifungal treatment.

Secondary fungal infection is a major complication in patients with sepsis-associated immunosuppression. However, sepsis-induced immune alterations related to fungal susceptibility have not been well characterized. To determine kinetic changes in the immune phenotype by determining the proportion of T cells, B cells and macrophages, and especially the expression of an immune exhaustion marker PD-1, in murine sepsis. In addition, sepsis -induced alterations of these immune cells were assessed in relation to susceptibility to secondary fungal infection. Cecal ligation and puncture (CLP) was used as a mouse sepsis model, with Candida albicans as the secondary systemic fungal infection. Splenic T cells, B cells and macrophages were assessed by flow cytometry. Alterations in T cell and B cell numbers and the proportion of PD-1 expressing T cells and B cells in CLP mice were not clearly related to susceptibility to secondary Candida infection. By contrast, changes in levels of CD86+-activated macrophages, and the proportion of the PD-1+ population among the CD86+ macrophages in CLP mice were found to be related to secondary fungal infection susceptibility. Macrophage activation and exhaustion might be a significant determinant in susceptibility to fungal infection, and outcomes of infection. This study provided more comprehensive knowledge pertinent to patient evaluation and therapeutics design in restoring host defenses against secondary fungal infection in those with sepsis.

Aspergillus flavusis one of the most common isolates from patients with fungal infections.Aspergillusinfection is usually treated with antifungal agents, but side effects of these agents are common. Trehalase is an essential enzyme involved in fungal metabolism, and the trehalase inhibitor, validamycin A, has been used to prevent fungal infections in agricultural products. In this study, we observed that validamycin A significantly increased trehalose levels inA. flavusconidia and delayed germination, including decreased fungal adherence. In addition, validamycin A and amphotericin B showed a combinatorial effect onA. flavusATCC204304 and clinical isolates with high minimum inhibitory concentrations (MICs) of amphotericin B using checkerboard assays. We observed that validamycin A and amphotericin B had a synergistic effect onA. flavusstrains resistant to amphotericin B. The MICs in the combination of validamycin A and amphotericin B were at 0.125 μg/mL and 2 μg/mL, respectively. The FICI of validamycin A and amphotericin B of these clinical isolates was about 0.25–0.28 with synergistic effects. No drug cytotoxicity was observed in human bronchial epithelial cells treated with validamycin A using LDH-cytotoxicity assays. In conclusion, this study demonstrated that validamycin A inhibited the growth ofA. flavusand delayed conidial germination. Furthermore, the combined effect of validamycin A with amphotericin B increasedA. flavuskilling, without significant cytotoxicity to human bronchial epithelial cells. We propose that validamycin A could potentially be usedin vivoas an alternative treatment forA. flavusinfections.

Despite therapeutic advances, multiple myeloma (MM) remains incurable, especially in relapsed/refractory (R/R) cases. B-cell maturation antigen (BCMA) is a key target for novel immunotherapies, including chimeric antigen receptor T-cell (CAR-T) therapies and bispecific T-cell engagers (BiTEs), which vary in efficacy, toxicity, and accessibility. To compare the efficacy and safety of BCMA-directed CAR-T therapies and BiTEs in R/R MM through a systematic review and meta-analysis. We systematically searched PubMed, Embase, and the Cochrane Library up to October 2, 2024, for studies evaluating BCMA-directed CAR-T or BiTEs therapies in R/R MM. Twenty-six studies comprising 2,246 patients were included. A random-effects meta-analysis and meta-regression were performed to assess pooled efficacy and safety outcomes and examine the impact of CAR-T constructs and patient-level characteristics. CAR-T therapies showed a higher overall response rate (ORR) of 84% and CR/stringent CR (CR/sCR) of 55%, compared to 65% and 41%, respectively, for BiTEs. Dual-targeted CAR-T therapies (e.g., anti-BCMA + anti-CD38/CD19) had the highest efficacy (ORR 92%). CAR-T was associated with more hematologic toxicity and cytokine release syndrome, while BiTEs had fewer severe events but higher infection rates. Meta-regression confirmed CAR-T significantly outperformed BiTEs. Unlike previous analyses, this study integrates interventional and real-world data, evaluates dual-target CAR-Ts, and offers detailed product- and subgroup-level comparisons. BCMA-targeted CAR-T therapies yield deeper responses but greater toxicity. BiTEs offer safer, though less potent, alternatives, supporting more personalized decisions in BCMA-directed immunotherapy for MM.