Junfei Huang, Yi Tong, Xinggui Yang, Yijiang Chen, Xiaoyu Wei, Xu Chen, Jinlan Li, Shijun Li
Leprosy is an ancient disease caused by Mycobacterium leprae (ML) that remains a public health problem in poverty-stricken areas worldwide. Although many ML detection techniques have been used, a rapid and sensitive tool is essential for the early detection and treatment of leprosy. Herein, we developed a rapid ML detection technique by combining multiple cross displacement amplification (MCDA) with a nanoparticle-based lateral flow biosensor (LFB), termed ML-MCDA-LFB. MCDA induced a rapid isothermal reaction using specific primers targeting the RLEP gene, and the LFB enabled instant visual amplicon detection...
September 22, 2023: ACS Infectious Diseases
Nicole L Inniss, Ján Kozic, Fengling Li, Monica Rosas-Lemus, George Minasov, Jiří Rybáček, Yingjie Zhu, Radek Pohl, Ludmilla Shuvalova, Lubomír Rulíšek, Joseph S Brunzelle, Lucie Bednárová, Milan Štefek, Ján Michael Kormaník, Erik Andris, Jaroslav Šebestík, Alice Shi Ming Li, Peter J Brown, Uli Schmitz, Kumar Saikatendu, Edcon Chang, Radim Nencka, Masoud Vedadi, Karla J F Satchell
A collaborative, open-science team undertook discovery of novel small molecule inhibitors of the SARS-CoV-2 nsp16-nsp10 2'- O -methyltransferase using a high throughput screening approach with the potential to reveal new inhibition strategies. This screen yielded compound 5a , a ligand possessing an electron-deficient double bond, as an inhibitor of SARS-CoV-2 nsp16 activity. Surprisingly, X-ray crystal structures revealed that 5a covalently binds within a previously unrecognized cryptic pocket near the S -adenosylmethionine binding cleft in a manner that prevents occupation by S -adenosylmethionine...
September 20, 2023: ACS Infectious Diseases
Farhan R Chowdhury, Brandon L Findlay
Antibiotic resistance is a major threat to global health, claiming the lives of millions every year. With a nearly dry antibiotic development pipeline, novel strategies are urgently needed to combat resistant pathogens. One emerging strategy is the use of sequential antibiotic therapy, postulated to reduce the rate at which antibiotic resistance evolves. Here, we use the soft agar gradient evolution (SAGE) system to carry out high-throughput in vitro bacterial evolution against antibiotic pressure. We find that evolution of resistance to the antibiotic chloramphenicol (CHL) severely affects bacterial fitness, slowing the rate at which resistance to the antibiotics nitrofurantoin and streptomycin emerges...
September 19, 2023: ACS Infectious Diseases
Ruonan Li, Yiwen Liu, Fuyou Zhou, Haijun Yang, Junkuo Li, Ningtao Dai, Wei Sun, Jinyu Kong, Shegan Gao
Studies have confirmed that the colonization of Porphyromonas gingivalis (Pg) could promote the malignant evolution of esophageal squamous cell carcinoma (ESCC). Since pathogenic microorganisms can promote malignant tumor proliferation by inhibiting programmed cell death factor 4 (PDCD4) and the decrease of PDCD4 activity can enhance the stemness of cancer cells, we here investigated the functional mechanism by which Pg promoted ESCC chemoresistance and malignancy through inhibiting PDCD4 and enriching cancer stem cells (CSCs)...
September 18, 2023: ACS Infectious Diseases
Michael K Fenwick, Alexandra R Reers, Yi Liu, Rachael Zigweid, Banumathi Sankaran, Janis Shin, Matthew A Hulverson, Bradley Hammerson, Elena Fernández Álvaro, Peter J Myler, Alexis Kaushansky, Wesley C Van Voorhis, Erkang Fan, Bart L Staker
Each year, approximately 50,000 children under 5 die as a result of diarrhea caused by Cryptosporidium parvum , a protozoan parasite. There are currently no effective drugs or vaccines available to cure or prevent Cryptosporidium infection, and there are limited tools for identifying and validating targets for drug or vaccine development. We previously reported a high throughput screening (HTS) of a large compound library against Plasmodium N -myristoyltransferase (NMT), a validated drug target in multiple protozoan parasite species...
September 18, 2023: ACS Infectious Diseases
John M Bennett, Kurt E Ward, Ryan K Muir, Stephanie Kabeche, Euna Yoo, Tomas Yeo, Grace Lam, Hao Zhang, Jehad Almaliti, Gabriel Berger, Franco F Faucher, Gang Lin, William H Gerwick, Ellen Yeh, David A Fidock, Matthew Bogyo
The Plasmodium proteasome is a promising antimalarial drug target due to its essential role in all parasite lifecycle stages. Furthermore, proteasome inhibitors have synergistic effects when combined with current first-line artemisinin and related analogues. Linear peptides that covalently inhibit the proteasome are effective at killing parasites and have a low propensity for inducing resistance. However, these scaffolds generally suffer from poor pharmacokinetics and bioavailability. Here we describe the development of covalent, irreversible, macrocyclic inhibitors of the Plasmodium falciparum proteasome...
September 15, 2023: ACS Infectious Diseases
Sara Ahmed, Sultan Chowdhury, James Gomez, Deborah T Hung, Tanya Parish
New drugs to treat tuberculosis which target intractable bacterial populations are required to develop shorter and more effective treatment regimens. The benzene amide ether scaffold has activity against intracellular Mycobacterium tuberculosis , but low activity against extracellular, actively replicating M. tuberculosis . We determined that these molecules have bactericidal activity against non-replicating M. tuberculosis but not actively replicating bacteria. Exposure to compounds depleted ATP levels in non-replicating bacteria and increased the oxygen consumption rate; a subset of molecules led to the accumulation of intrabacterial reactive oxygen species...
September 14, 2023: ACS Infectious Diseases
Rajneesh, Rahul Tiwari, Vishal K Singh, Awnish Kumar, Rohit P Gupta, Akhilesh K Singh, Vibhav Gautam, Rajiv Kumar
Malaria, caused by Plasmodium species, remains a major global health concern, causing millions of deaths annually. While the introduction of the RTS,S vaccine has shown promise, there is a pressing need for more effective vaccines due to the emergence of drug-resistant parasites and insecticide-resistant vectors. However, the complex life cycle and genetic diversity of the parasite, technical obstacles, limited funding, and the impact of the 2019 pandemic have hindered progress in malaria vaccine development...
September 14, 2023: ACS Infectious Diseases
Jayanta Haldar
No abstract text is available yet for this article.
September 13, 2023: ACS Infectious Diseases
Isabella de la Luz Quintana, Ankita Paul, Aniqa Chowdhury, Karen D Moulton, Suvarn S Kulkarni, Danielle H Dube
Glycans that coat the surface of bacteria are compelling antibiotic targets because they contain distinct monosaccharides that are linked to pathogenesis and are absent in human cells. Disrupting glycan biosynthesis presents a path to inhibiting the ability of a bacterium to infect the host. We previously demonstrated that O-glycosides act as metabolic inhibitors and disrupt bacterial glycan biosynthesis. Inspired by a recent study which showed that thioglycosides (S-glycosides) are 10 times more effective than O-glycosides at inhibiting glycan biosynthesis in mammalian cells, we crafted a panel of S-glycosides based on rare bacterial monosaccharides...
September 12, 2023: ACS Infectious Diseases
Zewen Wen, Cong Wang, Bing Bai, Xinyi Cao, Kewei Fan, Chunyou Hu, Peiyu Li, Qiwen Deng, Zhijian Yu
Streptococcus agalactiae is the major cause of invasive neonatal infections and is a recognized pathogen associated with various diseases in nonpregnant adults. The emergence and spread of antibiotic-resistant S. agalactiae necessitate the development of a novel antibacterial agent. Here, the potential antibacterial activities and mechanisms of ginkgolic acid C15:1 (GA (15:1)) from Ginkgo biloba against clinical S. agalactiae are characterized. The MIC50 and MIC90 values for GA (15:1) against 72 clinical S...
September 11, 2023: ACS Infectious Diseases
Rongguo Ren, Xiaofang Wang, Derek A Leas, Christian Scheurer, Sarah Hoevel, Monica Cal, Gong Chen, Longjin Zhong, Kasiram Katneni, Thao Pham, Rahul Patil, Diptesh Sil, Matthias J Walters, Thomas T Schulze, Andrew J Neville, Yuxiang Dong, Sergio Wittlin, Marcel Kaiser, Paul H Davis, Susan A Charman, Jonathan L Vennerstrom
We discovered dibenzannulated medium-ring keto lactams (11,12-dihydro-5 H -dibenzo[ b , g ]azonine-6,13-diones) as a new antimalarial chemotype. Most of these had chromatographic LogD7.4 values ranging from <0 to 3 and good kinetic solubilities (12.5 to >100 μg/mL at pH 6.5). The more polar compounds in the series (LogD7.4 values of <2) had the best metabolic stability (CLint values of <50 μL/min/mg protein in human liver microsomes). Most of the compounds had relatively low cytotoxicity, with IC50 values >30 μM, and there was no correlation between antiplasmodial activity and cytotoxicity...
September 11, 2023: ACS Infectious Diseases
Shiyi Shi, Mengxin Xu, Yining Zhao, Luozhu Feng, Qi Liu, Zhuocheng Yao, Yao Sun, Tieli Zhou, Jianzhong Ye
The goal of this study was to clarify the synergistic antibacterial activity of the combination of tigecycline (TGC) and rifampicin (RIF). Additionally, the study sought to investigate the impact of this combination on the development of mutational resistance and to assess its efficacy in an in vivo model using Galleria mellonella . Through a checkerboard test, we found that the combination of TGC and RIF showed synergistic antibacterial activity against carbapenem-resistant Klebsiella pneumoniae (CRKP). The fractional inhibition concentration index (FICI) was found to be ≤0...
September 5, 2023: ACS Infectious Diseases
Susana A Dias, Sandra N Pinto, Ana S Silva-Herdade, Marco Cavaco, Vera Neves, Luís Tavares, Manuela Oliveira, David Andreu, Ana Coutinho, Miguel A R B Castanho, Ana Salomé Veiga
The formation of biofilms is a common virulence factor that makes bacterial infections difficult to treat and a major human health problem. Biofilms are bacterial communities embedded in a self-produced matrix of extracellular polymeric substances (EPS). In this work, we show that vCPP2319, a polycationic peptide derived from the capsid protein of Torque teno douroucouli virus, is active against preformed Staphylococcus aureus biofilms produced by both a reference strain and a clinical strain isolated from a diabetic foot infection, mainly by the killing of biofilm-embedded bacteria...
September 5, 2023: ACS Infectious Diseases
Tobias M Milzarek, Milena Stevanovic, Dusan Milivojevic, Sandra Vojnovic, Denis Iliasov, Diana Wolf, Thorsten Mascher, Jasmina Nikodinovic-Runic, Tobias A M Gulder
The ambigols are cyanobacterial natural products characterized by three polychlorinated aromatic building blocks connected by biaryl and biaryl ether bridges. All ambigols known to date possess promising biological activities. Most significantly, ambigol A was reported to have antibacterial activity against Gram-positive bacteria, such as Bacillus megaterium and B. subtilis . We established a diverse compound library for in-depth biological evaluation building on our previous bio- and total synthetic research on this natural product family...
September 1, 2023: ACS Infectious Diseases
Seoung-Ryoung Choi, Prabagaran Narayanasamy
Menaquinone (MK) is an essential component in the oxidative phosphorylation pathway of Gram-positive bacteria. Drugs targeting enzymes involved in MK biosynthesis can prevent electron transfer, which leads to ATP starvation and thereby death of microorganisms. Previously, we reported a series of MenA inhibitors and demonstrated their antimicrobial activity against Gram-positive bacteria, including Methicillin-resistant Staphylococcus aureus (MRSA) and mycobacteria. These inhibitors were developed by mimicking demethylmenaquinone, a product of MenA enzymatic reaction in MK biosynthesis...
September 1, 2023: ACS Infectious Diseases
Carly Deusenbery, Olivia Carneiro, Carleigh Oberkfell, Anita Shukla
Methicillin-resistant Staphylococcus aureus (MRSA) infections are some of the most common antibiotic-resistant infections, often exacerbated by the formation of biofilms. Here, we evaluated six compounds, three common antibiotics used against MRSA and three antibiofilm compounds, in nine combinations to investigate the mechanisms of synergistic eradication of MRSA biofilms. Using metabolic assessment, colony enumeration, confocal fluorescence microscopy, and scanning electron microscopy, we identified two promising combinations of antibiotics with antibiofilm agents against preformed MRSA biofilms...
August 30, 2023: ACS Infectious Diseases
Dawson B Ling, William Nguyen, Oliver Looker, Zahra Razook, Kirsty McCann, Alyssa E Barry, Christian Scheurer, Sergio Wittlin, Mufuliat Toyin Famodimu, Michael J Delves, Hayley E Bullen, Brendan S Crabb, Brad E Sleebs, Paul R Gilson
With the resistance increasing to current antimalarial medicines, there is an urgent need to discover new drug targets and to develop new medicines against these targets. We therefore screened the Open Global Health Library of Merck KGaA, Darmstadt, Germany, of 250 compounds against the asexual blood stage of the deadliest malarial parasite Plasmodium falciparum, from which eight inhibitors with low micromolar potency were found. Due to its combined potencies against parasite growth and inhibition of red blood cell invasion, the pyridyl-furan compound OGHL250 was prioritized for further optimization...
August 28, 2023: ACS Infectious Diseases
Anlong Li, Jiajia Bao, Sijia Gao, Ying He, Xiaoping Nie, Felycia Fernanda Hosyanto, Xintong He, Tongxin Li, Lei Xu
Among the PLWH (people living with HIV) population, the risk of developing active tuberculosis (TB) is increasing. Active TB also accelerates the deterioration of PLWH's immune function and is one of the leading causes of death in the PLWH population. So far, accurate diagnosis of active TB in the PLWH population remains challenging. Through data analysis of HIV/TB co-infection in the GEO database, the differentially expressed genes as well as their related microRNA (miRNA) were acquired and were further verified through clinical blood samples...
August 25, 2023: ACS Infectious Diseases
Jing Xia, Yun Li, Cailu He, Can Yong, Li Wang, Huan Fu, Xiao-Long He, Zhou-Yu Wang, Dong-Fang Liu, Yuan-Yuan Zhang
A series of pleuromutilin derivatives containing an oxazolidinone skeleton were synthesized and evaluated in vitro and in vivo as antibacterial agents. Most of the synthesized derivatives exhibited potent antibacterial activities against three strains of Staphylococcus aureus (including MRSA ATCC 33591, MRSA ATCC 43300, and MSSA ATCC 29213) and two strains of Staphylococcus epidermidis (including MRSE ATCC 51625 and MSSE ATCC 12228). Compound 28 was the most active antibacterial agent in vitro (MIC = 0.008-0...
August 23, 2023: ACS Infectious Diseases
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