ACS Infectious Diseases

Colistin (COL), the last line of defense in clinical medicine, is an important therapeutic option against multidrug-resistant Gram-negative bacteria. In this context, the emergence of colistin-resistant (COL-R) bacteria mediated by broad-spectrum efflux pumps, mobile genetic elements, and biofilm formation poses a significant public health concern. In response to this challenge, a novel approach of combining COL with usnic acid (UA) has been proposed in this study. UA is a secondary metabolite derived from lichens and is well-known for its anti-inflammatory properties...

Primary amebic meningoencephalitis (PAM), a brain infection caused by a free-living ameba Naegleria fowleri , leads to an extensive inflammation of the brain and death within 1-18 (median 5) days after symptoms begin. Although natural products have played a significant role in the development of drugs for over a century, research focusing on identifying new natural product-based anti- N. fowleri agents is limited. We undertook a large-scale ATP bioluminescence-based screen of about 10,000 unique marine microbial metabolite mixtures against the trophozoites of N...

Antibacterial resistance poses a severe threat to public health; an anticipated 14-fold increase in multidrug-resistant (MDR) bacterial infections is expected to occur by 2050. Contrary to antibiotics, combination therapies are the standard of care for antiviral and anticancer treatments, as synergistic drug-drug interactions can decrease dosage and resistance development. In this study, we investigated combination treatments of a novel succinate dehydrogenase inhibitor (promysalin) with specific inhibitors of metabolism and efflux alongside a panel of clinically approved antibiotics in synergy studies...

Cilagicin is a Gram-positive active antibiotic that has a dual polyprenyl phosphate binding mechanism that impedes resistance development. Here we bioinformatically screened predicted non-ribosomal polypeptide synthetase encoded structures to search for antibiotics that might similarly avoid resistance development. Synthesis and bioactivity screening of the predicted structures that we identified led to three antibiotics that are active against multidrug-resistant Gram-positive pathogens, two of which, paenilagicin and virgilagicin, did not lead to resistance even after prolonged antibiotic exposure...

We report a maltose-derivatized fluorescence turn-on imaging probe, Mal-Cz , to detect E. coli and Staphylococci. The fluorescence turn-on is achieved through an intramolecular C-H insertion reaction of the perfluoroaryl azide-functionalized carbazole to give a fluorescent product. Confocal fluorescence microscopy confirmed the successful uptake of Mal-Cz by E. coli and Staphylococci upon photoactivation. The Mal-Cz probe could selectively detect E. coli and S. epidermidis in the presence of P. aeruginosa and M...

Pseudomonas aeruginosa (PA) is a Gram-negative, biofilm-forming bacterium and an opportunistic pathogen. The growing drug resistance of PA is a serious threat that necessitates the discovery of novel antibiotics, ideally with previously underexplored mechanisms of action. Due to their central role in cell metabolism, bacterial bioenergetic processes are of increasing interest as drug targets, especially with the success of the ATP synthase inhibitor bedaquiline to treat drug-resistant tuberculosis. Like Mycobacterium tuberculosis , PA requires F1 Fo ATP synthase for growth, even under anaerobic conditions, making the PA ATP synthase an ideal drug target for the treatment of drug-resistant infection...

The success of Staphylococcus aureus as a major cause for endovascular infections depends on effective interactions with blood-vessel walls. We have previously shown that S. aureus uses its wall teichoic acid (WTA), a surface glycopolymer, to attach to endothelial cells. However, the endothelial WTA receptor remained unknown. We show here that the endothelial oxidized low-density lipoprotein receptor 1 (LOX-1) interacts with S. aureus WTA and permits effective binding of S. aureus to human endothelial cells...

Despite colossal achievements in antibiotic therapy in recent decades, drug-resistant pathogens have remained a leading cause of death and economic loss globally. One such WHO-critical group pathogen is Salmonella . The extensive and inappropriate treatments for Salmonella infections have led from multi-drug resistance (MDR) to extensive drug resistance (XDR). The synergy between efflux-mediated systems and outer membrane proteins (OMPs) may favor MDR in Salmonella . Differential expression of the efflux system and OMPs (influx) and positional mutations are the factors that can be correlated to the development of drug resistance...

Leishmaniases are a collection of neglected tropical diseases caused by kinetoplastid parasites in the genus Leishmania . Current chemotherapies are severely limited, and the need for new antileishmanials is of pressing international importance. Bromodomains are epigenetic reader domains that have shown promising therapeutic potential for cancer therapy and may also present an attractive target to treat parasitic diseases. Here, we investigate Leishmania donovani bromodomain factor 5 ( Ld BDF5) as a target for antileishmanial drug discovery...

Currently, bone tuberculosis (TB) treatment largely involves lifelong drug prescriptions and surgical intervention, resulting in poor quality of life for patients. Therefore, the fabrication of injectable scaffolds to form a solid framework around the defective bone region is gaining importance over the extensive use of antimicrobial inhibitors. Herein, we synthesized a novel bone-adhesive and thermoresponsive hydrogel via conjugation of poly( N -isopropylacrylamide- co -glycidyl methacrylate) (PNIPAM- co -GMA) and cysteine (CYS)...

SARS-CoV-2 nsp14 functions both as an exoribonuclease (ExoN) together with its critical cofactor nsp10 and as an S -adenosyl methionine-dependent (guanine-N7) methyltransferase (MTase), which makes it an attractive target for the development of pan-anti-SARS-CoV-2 drugs. Herein, we screened a panel of compounds (and drugs) and found that certain compounds, especially Bi(III)-based compounds, could allosterically inhibit both MTase and ExoN activities of nsp14 potently. We further demonstrated that Bi(III) binds to both nsp14 and nsp10, resulting in the release of Zn(II) ions from the enzymes as well as alternation of protein quaternary structures...

The inhibition of efflux pumps is a promising approach to combating multidrug-resistant bacteria. We have developed a combined structure- and ligand-based model, using OpenEye software, for the identification of inhibitors of AcrB, the inner membrane protein component of the AcrAB-TolC efflux pump in Escherichia coli . From a database of 1391 FDA-approved drugs, 23 compounds were selected to test for efflux inhibition in E. coli . Seven compounds, including ivacaftor ( 25 ), butenafine ( 19 ), naftifine ( 27 ), pimozide ( 30 ), thioridazine ( 35 ), trifluoperazine ( 37 ), and meloxicam ( 26 ), enhanced the activity of at least one antimicrobial substrate and inhibited the efflux pump-mediated removal of the substrate Nile Red from cells...

Chagas disease (CD), caused by Trypanosoma cruzi ( T. cruzi ) protozoa, is a complicated parasitic illness with inadequate medical measures for diagnosing infection and monitoring treatment success. To address this gap, we analyzed changes in the metabolome of T. cruzi -infected mice via liquid chromatography tandem mass spectrometry of clinically accessible biofluids: saliva, urine, and plasma. Urine was the most indicative of infection status across mouse and parasite genotypes. Metabolites perturbed by infection in urine include kynurenate, acylcarnitines, and threonylcarbamoyladenosine...

Wax esters (WEs) are neutral lipids that are produced by many different bacteria as potential carbon and energy storage compounds. Comparatively little is known about the role of WE in pathogenic bacteria. The opportunistic pathogen Acinetobacter baumannii is a major cause of hospital-acquired infections worldwide. Salt and desiccation resistance foster A. baumannii infections such as urinary tract infections and allow for reinfection when bacteria are taken up from dry surfaces in the hospital environment...

The objective of this study is to take the initial steps toward developing novel antibiotics to counteract the escalating problem of antimicrobial and bacterial persistence, particularly in relation to biofilms. Our approach involves emulating the structural characteristics of cationic antimicrobial peptides. To circumvent resistance development, we have designed a library of bis-benzimidazolium salts that selectively target the microbial membranes in a nonspecific manner. To explore their structure-activity relationship, we conducted experiments using these compounds on various pathogens known for their resistance to conventional antibiotics, including Gram-positive methicillin - resistant Staphylococcus aureus ( MRSA ), vancomycin - resistant Enterococcus faecium ( VRE ), and Gram-negative Escherichia coli ( E...

Here, we employed an integrated metabolomics and transcriptomics approach to investigate the molecular mechanism(s) of action of ceftazidime/avibactam against a pan-drug-resistant K. pneumoniae clinical isolate from a patient with urinary tract infection. Ceftazidime/avibactam induced time-dependent perturbations in the metabolome and transcriptome of the bacterium, mainly at 6 h, with minimal effects at 1 and 3 h. Metabolomics analysis revealed a notable reduction in essential lipids involved in outer membrane glycerolipid biogenesis...

African swine fever (ASF) is caused by the African swine fever virus (ASFV) and is a highly contagious, acute, febrile disease that has high morbidity and mortality rates in domestic and wild swine. However, a safe and effective vaccine against ASF remains unavailable as single antigens fail to provide sufficient protection. Therefore, a combination of multiple antigens with an efficient delivery system might be an alternative strategy. Herein, a de novo-designed antigen with multiple T-cell epitopes (TEPs) of ASFV was conjugated for surface display on self-assembled nanoparticles (NPs) of Aquifex aeolicus lumazine synthase (AaLS) and Quasibacillus thermotolerans encapsulin (QT) through the SpyCatcher/SpyTag system to construct nanovaccines (TEP-Spy-NPs)...

Antibodies play a vital role in the immune response to infectious diseases and can be administered passively to protect patients. In the case of Cryptococcus neoformans , a WHO critical priority fungal pathogen, infection results in antibodies targeting capsular glucuronoxylomannan (GXM). These antibodies yield protective, non-protective, and disease-enhancing outcomes when administered passively. However, it was unknown how these distinct antibodies recognized their antigens at the molecular level, leading to the hypothesis that they may target different GXM epitopes...

Due to excessive use or abuse in the food industry, agriculture, and medicine, many pathogens are developing resistance against conventional antibiotics. Antimicrobial peptides (AMPs) hold promise as effective therapeutic options for the treatment of bacterial infections. Herein, a novel cathelicidin antimicrobial peptide (Zs-CATH) was identified from the tree frog Zhangixalus smaragdinus . Zs-CATH mainly adopted an amphipathic β-sheet structure in a membrane-mimetic environment. It showed broad-spectrum antibacterial activity against Gram-positive and Gram-negative bacteria in vitro and significantly protected mice from lethal infections induced by Gram-negative bacteria Escherichia coli ATCC 25922 or Gram-positive bacteria Staphylococcus aureus ATCC 25923 in vivo ...

The latest RNA genomic mutation of SARS-CoV-2 virus, termed the Omicron variant, has generated a stream of highly contagious and antibody-resistant strains, which in turn led to classifying Omicron as a variant of concern. We systematically collected Raman spectra from six Omicron subvariants available in Japan (i.e., BA.1.18, BA.2, BA.4, BA.5, XE, and BA.2.75) and applied machine-learning algorithms to decrypt their structural characteristics at the molecular scale. Unique Raman fingerprints of sulfur-containing amino acid rotamers, RNA purines and pyrimidines, tyrosine phenol ring configurations, and secondary protein structures clearly differentiated the six Omicron subvariants...