Hongkai Bi

Helicobacter pylori ( H. pylori ) is a significant global human pathogen intricately linked to gastritis, peptic ulcers, and gastric cancer. The escalating challenge of antimicrobial resistance and the adverse effects of conventional antibiotics on the gut microbiome necessitate the development of novel, targeted therapeutics. In this study, we demonstrate that carnosic acid (CA), a natural compound derived from traditional Chinese medicine, exhibits potent and specific anti‐ H. pylori activity in vitro, with no detectable resistance observed after prolonged serial passaging. CA also displayed enhanced antibacterial efficacy under physiologically relevant acidic conditions, correlating with its strong inhibition of urease, a key colonization factor for H. pylori . Beyond urease suppression, CA acted through multiple mechanisms, including inhibiting biofilm formation and disrupting mature biofilms, impairing bacterial motility, and compromising cell membrane integrity. In vivo, the combination of CA and omeprazole achieved superior eradication in a mouse model of multidrug‐resistant H. pylori infection compared to standard triple therapy. Furthermore, CA treatment showed negligible toxicity to host tissues and minimal disruption to the diversity and composition of the gut microbiota. These findings position CA as a promising lead compound against drug‐resistant H. pylori , offering a multi‐targeting and microbiota‐friendly strategy to combat this pathogen.

Fungal infections pose a significant global health burden, accounting for approximately 1.5 million deaths annually [1]. Among fungal pathogens, Candida species are the predominant causative agents...

The β-ketoacyl-acyl carrier protein (ACP) synthases are pivotal elongation enzymes that catalyze the condensation of acyl-CoA or acyl-ACP with malonyl-ACP to produce β-ketoacyl-ACP. Among these, the homologous enzymes FabH (β-ketoacyl-ACP synthase III) and the recently characterized BioZ play crucial roles, initiating the biosynthetic pathways for fatty acids and biotin, respectively. FabH primarily utilizes acetyl-CoA as the primer substrate, whereas BioZ exclusively condenses the longer glutaryl-CoA, which contains a charged ω-carboxyl group. Despite their similar catalytic mechanisms, the molecular bases for the strict substrate specificities remain undetermined. Here, we report crystal structures of the BioZ: glutaryl-CoA cocrystalized complexes and demonstrate the ability to swap the physiological functions and substrate specificities between FabH and BioZ. This functional interchange was achieved by grafting the β8-α9 loop plus residue Ala317 of Agrobacterium tumefaciens BioZ to Escherichia coli FabH, resulting in a shift in substrate preference from acetyl-CoA to glutaryl-CoA. The reverse manipulations of BioZ resulted in FabH activity. These data identify the structural elements as the minimal determinants of substrate specificity and enzyme function. These findings provide valuable insights into the molecular mechanisms of substrate recognition and catalysis by FabH and BioZ and offer a foundation for the development of targeted therapeutic strategies against these enzymes.

Helicobacter pylori, a globally significant pathogen, plays a central etiological role in diverse gastric pathologies ranging from chronic gastritis and peptic ulcers to gastric adenocarcinoma. Although conventional antibiotics effectively inhibit or kill growing helical H. pylori, metabolically dormant coccoid forms of H. pylori exhibit considerable tolerance, posing a persistent and clinically significant challenge. Here, we report napabucasin (2-acetylfuro-1,4-naphthoquinone) as a redox-cycling antibiotic with potent bactericidal activity against both drug-resistant helical and coccoid forms of H. pylori. Notably, napabucasin does not induce acquired resistance in vitro and demonstrates superior efficacy compared to standard triple therapy in murine infection models. Mechanistic studies reveal that napabucasin acts through 2-oxoglutarate:acceptor oxidoreductase (OOR)-catalyzed futile redox cycling, generating bactericidal levels of reactive oxygen species (ROS). Compared to menaquinone 6, a proposed physiological electron acceptor, napabucasin exhibits enhanced oxidative capacity. Structural, biochemical, and microbiological analyses identify Leu44 and Lys46 within the OorD subunit as critical residues for napabucasin recognition and catalysis. These findings establish OOR-mediated redox cycling as a robust antimicrobial strategy that sustains endogenous ROS production to combat refractory H. pylori infections.

Helicobacter pylori (H. pylori) is a group‐1 definite pathogenic carcinogen that infects approximately half of the global population, yet no species‐specific chemotherapy has yet been developed. It is previously discovered that H. pylori encodes an atypical dehydrogenase/isomerase FabX in the Type‐II fatty acid biosynthesis pathway to produce unsaturated fatty acids (UFA) as well as superoxide (ROS). Here, it is demonstrated that FabX is essential for H. pylori growth and gastric colonization by retaining UFA synthesis and producing ROS, respectively, and is a species‐specific anti‐H. pylori drug target. The first small molecule inhibitor FBX‐1991 against FabX, which inhibits the enzymatic activity with an IC₅₀ value of 0.158 × 10⁻⁶ m in vitro, is developed. FBX‐1991 binds inside the catalytic tunnel of FabX, disrupts the conformation of the key catalytic loop, and prevents the insertion of the acyl substrate for catalysis. Further in vivo studies suggest that FBX‐1991 inhibits the H. pylori growth by partially inhibiting UFA synthesis and ROS excretion through targeting FabX. This study identifies a species‐specific anti‐H. pylori drug target, FabX, and discovers the first highly potent and selective FabX inhibitor against H. pylori infection, which provides the molecular basis for developing species‐specific anti‐H. pylori chemotherapy.

Background: Multidrug-resistant bacteria (MDRB) represent a significant global challenge due to their high mortality rates, substantial economic burden, and rapid spread. Traditional triple or quadruple therapies have demonstrated limited efficacy as a result of increasing drug resistance. Thus, it is urgent to develop novel anti-MDRB drugs with high efficiency and low toxicity. Objectives: To isolate and identify the dihydrostilbenoids and flavones from the aerial part of Glycyrrhiza uralensis (Fabaceae) and to screen their antimicrobial activities. Materials and methods: The aerial part of G. uralensis was extracted with 75% aqueous EtOH. The crude extract was repeatedly isolated by macroporous resin, silica gel, Sephadex LH-20, C ₁₈ -MPLC, and MCI-MPLC, which were then purified by semipreparative RP-HPLC to obtain monomer compounds. The structures of the isolates were assigned by a combination of optical rotations, UV spectra, nuclear magnetic resonance, and high-resolution electrospray ionization mass spectrometry, and the absolute configurations of compounds 2 , 3 , and 7 were further confirmed by electronic circular dichroism calculations. Subsequently, we investigated their antimicrobial activities by the broth microdilution method. Results: Seventeen previously undescribed phenolic compounds ( 1–17 ) and 26 known analogs ( 18–43 ), including dihydrostilbenoids, flavones, and dihydroflavones, were identified from the aerial part of G. uralensis . In vitro, antimicrobial bioassays demonstrated that compound 31 displayed the strongest inhibitory effect against 4 drug-resistant Helicobacter pylori strains (MIC = 2–4 μg/mL), comparable to metronidazole (MIC = 1–32 μg/mL). Additionally, compounds 10 , 13 , and 15 demonstrated bactericidal activity against Staphylococcus aureus (MIC = 4 μg/mL), while compounds 15 and 22 exhibited inactivation effects against Mycobacterium smegmatis , Enterococcus faecium , and E. faecalis (MIC = 4–8 μg/mL). Conclusions: These monomeric compounds with antimicrobial activities were isolated from the aerial parts of G. uralensis , providing valuable insights into the potential anti-MDRB properties of its nonmedicinal parts.