ACS Infectious Diseases最新文献

AntibioticDB (https://www.antibioticdb.com/), originally established in 2017 and since 2021 led by the Global Antibiotic Research & Development Partnership (GARDP), is a freely available database of antibacterial agents to facilitate research and development of new antibacterial therapeutics. Here, we describe a new release of AntibioticDB that has been significantly expanded and updated with the aid of user feedback and which offers additional functionality through a redesigned web portal. Improvements include reciprocal integration with the IUPHAR/BPS Guide to Pharmacology (https://www.guidetopharmacology.org), capturing of compound structure information in the form of standard chemical identifiers (canonical and isomeric SMILES, InChI, and InChI Key), chemical 2D structure images, and harmonizing terminology to optimize database searching. Ongoing curation efforts have increased the number of individual entries to >3,500, a process driven mostly by a significant expansion of historical natural product antibiotics that were previously under-represented in the database. The database is continuously updated by mining the published literature and capturing newly discovered antibacterial compounds as they are reported, making AntibioticDB the most complete global resource on antibacterial agents.

Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen for which new antimicrobial strategies are urgently needed. To facilitate the establishment of the infection, P. aeruginosa produces a remarkable assortment of both cell-associated and extracellular virulence factors. The expression of numerous virulence traits is regulated by the pqs quorum sensing (QS) system, which relies on multiple enzymes for the biosynthesis of 2-alkyl-4-quinolone (AQ) signal molecules and on the transcriptional regulator PqsR, whose activity is triggered by AQ binding. Herein, we report on the design and synthesis of novel quinazolinone-based PqsR modulators, which led to the identification of two novel compounds endowed with anti-PqsR activity in the submicromolar range. Additionally, these derivatives inhibited the production of PqsR-controlled virulence factors in laboratory strains and clinical isolates of P. aeruginosa.

The emergence of multidrug resistance underscores the urgent need to develop new classes of antibiotics with novel mechanisms of action. The majority of antibiotics currently in use are designed to target Gram-positive bacteria. However, Gram-negative bacteria can circumvent the effects of the majority of drug molecules due to the unique composition of their outer membrane. This additional layer functions as a formidable barrier, impeding the penetration of compounds into the cell. In this context, several strategies have been identified to facilitate the accumulation of compounds in Gram-negative bacteria. This review provides a concise overview of the physicochemical properties that can assist in the entry and accumulation of compounds in Gram-negative bacteria, and it also covers various approaches for targeting or circumventing the outer membrane-mediated barrier of Gram-negative pathogenic bacteria.

Medicinal chemistry has evolved over the years, to meet challenges in the field of therapeutic development. Since the dawn of the antibiotic era, this field has stepped up and contributed extensively to antibacterial drug development, right from developing better and more potent analogues, to improving pharmacokinetics and stability, from overcoming resistance, to facilitating better delivery through formulations. The contributions of medicinal chemistry, across these and many other areas, have shaped medicine, and facilitated its transition from an empirical discipline to a rigorous science, with significant progress being made in the last five decades. Commemorating the 150 years of the American Chemical Society, this Viewpoint highlights the central role of medicinal chemistry in shaping antibacterial drug discovery over the decades, and explores the emerging paradigms which are bound to influence this field.

Sepsis is defined as a life-threatening condition that arises when the body’s dysregulated inflammatory response to infection causes injury to its own tissues and organs. Early and late mediators of sepsis are lipopolysaccharide (LPS) from bacteria and the alarmin high mobility group box 1 (HMGB1), respectively. In this Perspective, the role of host defense peptides (HDPs) in reducing proinflammatory cytokines tied to sepsis is presented. The multimodal bactericidal and immunomodulatory activities of HDPs imbue these molecules with tremendous therapeutic potential to tackle the leading cause of death worldwide.

Lysine acylation is a posttranslational modification (PTM) conserved in all domains of life and is essential for regulating diverse biological processes. Traditional methods for investigating acylation rely on anti-acyl-lysine antibodies, which are costly and time-consuming and often exhibit variable affinity. To remedy these pitfalls, we developed an antibody-free method for bacterial acylome enrichment using bioorthogonal click chemistry coupled with tandem mass spectrometry. We applied this approach to the pathogens Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA) to explore the biological significance of acylation in each organism. We characterized the acetylome, propionylome, and butyrylome in P. aeruginosa UCBPP-PA14 and the acetylome and propionylome in MRSA. Comparative analyses revealed unique PTM dynamics showing that acylation regulated a wide range of cellular functions, including metabolism, antibiotic resistance, virulence, and stress response. This work establishes the first antibody-free enrichment method for defining bacterial acylomes and provides new insight into global lysine acylation networks in pathogenic bacteria.

Antimicrobial resistance (AMR) is a significant global health challenge, undermining the effectiveness of existing therapies and driving substantial mortality and economic burdens worldwide. In the development of novel antimicrobials, pharmacokinetic/pharmacodynamic (PK/PD) analysis provides a critical bridge between preclinical studies and clinical application, guiding the design of optimal dosing regimens for clinical trials. The use of antibiotic adjuvants that can restore or enhance the antimicrobial activity of clinically employed antibiotics against AMR-associated pathogens presents a promising strategy to combat AMR. Although β-lactamase inhibitors are the only antibiotic adjuvant class that are currently clinically employed, emerging adjuvant therapies have shown promise in preclinical and clinical development studies. PK/PD relationships of antibiotic adjuvants in combination with antibiotics require thorough investigation in mouse infection models as a prerequisite for progression into clinical trials. As exemplified by β-lactamase inhibitors, conventional MIC-based approaches are not appropriate for the characterization of adjuvant PK/PD relationships, due to the lack of intrinsic antimicrobial activity of the adjuvant. Modified PK/PD parameters using threshold concentrations (C_T) or instantaneous MIC (MIC_i) values are discussed as potentially more suitable approaches.

The escalating global crisis of antibiotic resistance demands the urgent development of innovative antibacterial agents with new mechanisms of action. Herein, we report the design and characterization of self-derived antibacterial peptides from the N-terminal region of Escherichia coli OmpF, a typical β-barrel outer membrane protein (OMP). These peptides exhibit cellular lethality when endogenously expressed, and one of them, having 42 amino acids in length (designated as OmpF7), directly kills outer membrane-permeabilized E. coli cells. Mechanistically, OmpF7 interacts with periplasmic chaperones SurA and Skp in vitro, disrupts both in vitro and in vivo SurA–OmpF interactions, decreases the level of folded OmpF, and severely influences cell morphology but has little detrimental effect on the cytoplasmic membrane and behaves distinctively from polymyxin B, a well-known antibacterial peptide. Importantly, OmpF7 directly kills Gram-negative pathogens (e.g., Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumannii, and Salmonella typhimurium) and multidrug-resistant clinical isolates of E. coli when it is conjugated with a membrane-penetrating peptide or combined with a nontoxic adjuvant carvacrol. These observations suggest that OmpF7 exerts its lethal effects by saturating the OMP-binding sites of SurA/Skp and thus disrupting chaperone-mediated OMP biogenesis, eventually leading to cell death. Our study not only validates periplasmic chaperone–OMP interactions as promising drug targets against Gram-negative pathogens but also provides a chemical biology tool for probing the OMP biogenesis mechanism.

Intracellular bacterial infections remain a global health challenge due to their insidious and persistent nature. This review focuses on host–pathogen interactions, referring to the dynamic struggle between host immune defenses and bacterial invasion/survival mechanisms. A thorough understanding of host cell bactericidal mechanisms, as well as the invasion and evasion strategies employed by intracellular bacteria, is essential for developing novel antibacterial agents. Crucially, traditional antibiotics often fail due to poor membrane permeability, rapid efflux, or suboptimal subcellular accumulation, leading to treatment failure and resistance. To break this deadlock, peptide-based therapeutics offer a transformative frontier through: (1) precision delivery via cell-penetrating peptides (CPPs); (2) multimodal bactericidal mechanisms to minimize resistance; and (3) host-directed therapies that reactivate innate defense pathways. Furthermore, we highlight optimization strategies ranging from rational chemical design to AI-driven generative discovery. To facilitate clinical translation, we conclude by outlining future directions: integrating ultralarge library screening (e.g., phage/mRNA display) to expand discovery; employing chemical modifications and nanoencapsulation to overcome metabolic fragility; and developing stimuli-responsive “smart” platforms for spatiotemporally precise, low-toxicity delivery. Finally, implementing compartment-specific PK/PD models to quantify subcellular drug exposure is essential.

The interactions among the host’s circular RNAs (circRNAs), microRNAs (miRNAs), and target genes are crucial for antibacterial resistance and intracellular pathogen clearance. However, this process remains poorly understood during Mycobacterium tuberculosis (M.tb) infection. Our previous study identified hsa_circ_000477, a novel circRNA formed by the NRIP1 gene on human chromosome 21, which was upregulated in M.tb-infected THP-1 macrophages. The present study systematically investigated the effect of hsa_circ_0004771 on M.tb infection and the underlying molecular mechanism. First, hsa_circ_0004771 was demonstrated to inhibit M.tb intracellular survival in macrophages. To identify its target miRNAs, multiple algorithms were used for computational prediction, and qPCR, dual-luciferase reporter assays, and RNA fluorescence in situ hybridization (FISH) were performed to confirm that miR-3921 was the primary target miRNA of hsa_circ_0004771. Further computational analyses across multiple algorithms─such as miRDB, TarBase, TargetScan, and microT-CDS─and validation with the above-mentioned methods, TREM1 was identified as the target of miR-3921. The results showed that an elevated level of TREM1 expression increased P65 phosphorylation levels, thereby enhancing IL-1β secretion. In conclusion, we identified a novel host defense mechanism in M.tb-infected THP-1 cells: the hsa_circ_0004771/miR-3921/TREM1 axis suppresses bacterial survival by promoting proinflammatory IL-1β production. These findings revealed a novel mechanism involved in host defense against M.tb infection.