Wei Huang

The past decade has witnessed the recognition of antibiotic resistance as an emerging threat to public health. Polymyxin B (PMB) is a last-resort antibiotic against multidrug-resistant (MDR) Gram-negative bacteria, but it has nephrotoxicity. A cocktail with molecules to sensitize microbes to PMB is an effective approach to rescue and expand its clinical application range. Tuspetinib (TUS) is a selective FMS-like tyrosine kinase 3 (FLT3) inhibitor with activity against acute myeloid leukemia (AML) and a favorable safety profile. In this study, we found that TUS can enhance the antibacterial activity of PMB against Klebsiella pneumoniae and its clinical PMB-resistant isolates. We also revealed the mechanism by which TUS inhibits the activity of GlcNAc6P deacetylase (NagA) and clarified the association between NagA and PMB resistance. Finally, we demonstrated the efficacy of TUS plus PMB therapy in a mouse model of pulmonary infection with a clinical PMB-resistant K. pneumoniae isolate. In all, this work discovers a promising drug combination strategy based on PMB and TUS and underlies the special mode of action that involves inhibiting the activity of NagA.

The limitations of existing drugs and the development of drug resistance make it urgent to develop new drugs against methicillin-resistant Staphylococcus aureus (MRSA). The re-development of the antibacterial activity of drugs that have already been proven safe for human use is an effective way. In this study, we discovered that the Src homology region 2 domain-containing phosphatase-1 (SHP-1) agonist SC-43, exhibits potent activity against Gram-positive bacteria, including MRSA. The mode of action studies revealed that SC-43 inhibits the key enzyme coproporphyrin ferrochelatase (CpfC) of the coproporphyrin-dependent (CPD) heme synthesis pathway and interferes with the bacterial porphyrin metabolism. The determination of the structure of CpfC derived from S. aureus (SA _CpfC ) in this study allowed us to reveal the inhibitory effect of SC-43 at the molecular level. Animal experiments showed that SC-43 has the potential to become a new anti-MRSA drug. In conclusion, this study discovered a new anti-MRSA activity of a drug currently undergoing clinical trials and simultaneously verified the feasibility of developing new anti-Gram-positive bacteria drugs by inhibiting the CPD pathway.

Background: Klebsiella pneumoniae (KP) infections present a significant clinical challenge and are frequently associated with elevated drug resistance. The use of phage therapy has resurged in response to escalating antibiotic resistance. This study aimed to address the multidrug resistance crisis in intensive care units by exploring the use of ceftazidime/avibactam (CAZ/AVI), a widely used clinical antimicrobial agent, in conjunction with phage therapy. Materials and Methods: We screened a clinical strain of KP from ICU and successfully isolated phage N22 from hospital wastewater. We conducted an in-depth analysis of the physiological and biochemical properties of phage N22 and determined its optimal multiplicity of infection with the clinical KP strain. The inhibitory effects of phage N22 in combination with CAZ/AVI on biofilm formation were investigated. Comparative efficacies of these combinations were evaluated using a Galleria mellonella (G. mellonella) model. Results: Phage N22 inhibited KP biofilm formation. The impact of varying phage N22 concentrations when used alongside CAZ/AVI was examined, and the combination of phage N22 and CAZ/AVI was more effective against KP than CAZ/AVI alone. Conclusion: This study provides a preliminary investigation into the effects of combining CAZ/AVI with phage therapy, highlighting its potential significance in developing novel therapeutic strategies for bacterial infections resistant to CAZ/AVI. The findings underscore the importance of advancing highly effective phage agents as alternative treatment modalities for patients with infections refractory to conventional antibiotics.

Objectives: This study describes the detection and tracking of emergency neurosurgical cross-transmission infections with carbapenem-resistant Klebsiella oxytoca (CRKO).Methods: We conducted an epidemiological investigation and a rapid screening of 66 surveillance samples using the chromogenic selective medium. Two CRKO isolates from infected patients and three from the preoperative shaving razors had similar resistance profiles identified by the clinical laboratory.Results: The whole genome sequencing (WGS) results identified all isolates as Klebsiella michiganensis (a species in the K. oxytoca complex) with sequence type 29 (ST29) and carrying resistance genes bla_KPC-2 and bla_OXY-5, as well as IncF plasmids. The pairwise average nucleotide identity values of 5 isolates ranged from 99.993% to 99.999%. Moreover, these isolates displayed a maximum genetic difference of 3 among 5,229 targets in the core genome multilocus sequence typing scheme, and the razors were confirmed as the contamination source. After the implementation of controls and standardized shaving procedures, no new CRKO infections occurred.Conclusion: Contaminated razors can be sources of neurosurgical site infections with CRKO, and standard shaving procedures need to be established. Chromogenic selective medium can help rapidly identify targeted pathogens, and WGS technologies are effective mean in tracking the transmission source in an epidemic or outbreak investigation. Our findings increase the understanding of microbial transmission in surgery to improve patient care quality.

The development of new antibiotics continues to pose challenges, particularly considering the growing threat of multidrug-resistant Staphylococcus aureus. Structurally diverse natural products provide a promising source of antibiotics. Herein, we outline a concise approach for the collective asymmetric total synthesis of polycyclic xanthene myrtucommulone D and five related congeners. The strategy involves rapid assembly of the challenging benzopyrano[2,3-a]xanthene core, highly diastereoselective establishment of three contiguous stereocenters through a retro-hemiketalization/double Michael cascade reaction, and a Mitsunobu-mediated chiral resolution approach with high optical purity and broad substrate scope. Quantum mechanical calculations provide insight into stereoselective construction mechanism of the three contiguous stereocenters. Additionally, this work leads to the discovery of an antibacterial agent against both drug-sensitive and drug-resistant S. aureus. This compound operates through a unique mechanism that promotes bacterial autolysis by activating the two-component sensory histidine kinase WalK. Our research holds potential for future antibacterial drug development.

Introduction: This study aims to establish a comprehensive, multi-level approach for tackling tropical diseases by proactively anticipating and managing Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) within the initial 14 days of Intensive Care Unit (ICU) admission. The primary objective is to amalgamate a diverse array of indicators and pathogenic microbial data to pinpoint pivotal predictive variables, enabling effective intervention specifically tailored to the context of tropical diseases. Methods: A focused analysis was conducted on 1733 patients admitted to the ICU between December 2016 and July 2019. Utilizing the Least Absolute Shrinkage and Selection Operator (LASSO) regression, disease severity and laboratory indices were scrutinized. The identified variables served as the foundation for constructing a predictive model designed to forecast the occurrence of PICS. Results: Among the subjects, 13.79% met the diagnostic criteria for PICS, correlating with a mortality rate of 38.08%. Key variables, including red-cell distribution width coefficient of variation (RDW-CV), hemofiltration (HF), mechanical ventilation (MV), Norepinephrine (NE), lactic acidosis, and multiple-drug resistant bacteria (MDR) infection, were identified through LASSO regression. The resulting predictive model exhibited a robust performance with an Area Under the Curve (AUC) of 0.828, an accuracy of 0.862, and a specificity of 0.977. Subsequent validation in an independent cohort yielded an AUC of 0.848. Discussion: The acquisition of RDW-CV, HF requirement, MV requirement, NE requirement, lactic acidosis, and MDR upon ICU admission emerges as a pivotal factor for prognosticating PICS onset in the context of tropical diseases. This study highlights the potential for significant improvements in clinical outcomes through the implementation of timely and targeted interventions tailored specifically to the challenges posed by tropical diseases.

Quorum sensing (QS) is considered an appealing target for interference with bacterial infections. beta-Adrenergic blockers are promising anti-QS agents but do not have antibacterial activity. We assessed the potential ability of adrenergic receptor inhibitors to enhance the antibacterial activity of polymyxin B (PB) against Klebsiella pneumoniae and determined that dronedarone has the most potent activity both in vitro and in vivo. We found that dronedarone increases the thermal stability of LuxS, decreases the production of AI-2, and affects the biofilm formation of K. pneumoniae. We also identified the direct binding of dronedarone to LuxS. However, the mechanism by which dronedarone enhances the antibacterial activity of PB has not been elucidated and is worthy of further exploration. Our study provides a basis for the future development of drug combination regimens.

Objective: The objective of this study was to utilize LASSO regression (Least Absolute Shrinkage and Selection Operator Regression) to identify key variables in septic patients and develop a predictive model for intensive care unit (ICU) mortality. Methods: We conducted a cohort consisting of septic patients admitted to the ICU between December 2016 and July 2019. The disease severity and laboratory index were analyzed using LASSO regression. The selected variables were then used to develop a model for predicting ICU mortality. AUCs of ROCs were applied to assess the prediction model, and the accuracy, sensitivity and specificity were calculated. Calibration were also used to assess the actual and predicted values of the predictive model. Results: A total of 1733 septic patients were included, among of whom 382 (22%) died during ICU stay. Ten variables, namely mechanical ventilation (MV) requirement, hemofiltration (HF) requirement, norepinephrine (NE) requirement, septicemia, multiple drug-resistance infection (MDR), thrombocytopenia, hematocrit, red-cell deviation width coefficient of variation (RDW-CV), C-reactive protein (CRP), and antithrombin (AT) III, showed the strongest association with sepsis-related mortality according to LASSO regression. When these variables were combined into a predictive model, the area under the curve (AUC) was found to be 0.801. The AUC of the validation group was 0.791. The specificity of the model was as high as 0.953. Within the probability range of 0.25 to 0.90, the predictive performance of the model surpassed that of individual predictors within the cohort. Conclusion: Our findings suggest that a predictive model incorporating the variables of MV requirement, HF requirement, NE requirement, septicemia, MDR, thrombocytopenia, HCT, RDW-CV, CRP, and AT III exhibiting an 80% likelihood of predicting ICU mortality in sepsis and demonstrates high accuracy.