Chemistry; Biosynthesis
Chemistry; BiosynthesisNybomycin Inhibits both Fluoroquinolone-Sensitive and Fluoroquinolone-Resistant Escherichia coli DNA GyraseBacterial type II topoisomerases, DNA gyrase and topoisomerase IV, are targets of many antibiotics, including fluoroquinolones (FQs). Unfortunately, a number of bacterial species easily acquire resistance to FQs by mutations in either DNA gyrase or topoisomerase IV genes.
Mechanisms of Action: Physiological Effects
Mechanisms of Action: Physiological EffectsPerillyl Alcohol Reduces Parasite Sequestration and Cerebrovascular Dysfunction during Experimental Cerebral MalariaCerebral malaria (CM) is a severe immune vasculopathy which presents a high mortality rate (15 to 20%), despite the availability of artemisinin-based therapy. More effective immunomodulatory and/or antiparasitic therapies are urgently needed.
Mechanisms of Action: Physiological EffectsThe Promises and Limitations of N-Acetylcysteine as a Potentiator of First-Line and Second-Line Tuberculosis DrugsN-Acetylcysteine (NAC) is most commonly used for the treatment of acetaminophen overdose and acetaminophen-induced liver injury. In patients infected with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), NAC is given to treat hepatotoxicity induced by TB drugs.
Mechanisms of Action: Physiological EffectsA 2-Pyridone Amide Inhibitor of Transcriptional Activity in Chlamydia trachomatisChlamydia trachomatis is a strict intracellular bacterium that causes sexually transmitted infections and eye infections that can lead to lifelong sequelae. Treatment options are limited to broad-spectrum antibiotics that disturb the commensal flora and contribute to selection of antibiotic-resistant bacteria.
Mechanisms of Action: Physiological EffectsInhibitory Effect of Host Ocular Microenvironmental Factors on Chlorhexidine Digluconate ActivityAcanthamoeba spp. are free-living protozoans that cause a serious human eye disease called Acanthamoeba keratitis (AK). Several new and effective medical therapies for AK patients remain highly debated, and therefore, chlorhexidine digluconate (CHG) is still considered one of the first lines of treatment for AK patients.
Mechanisms of Resistance
Mechanisms of ResistanceThe Plasmid-Mediated Kluyvera-Like arnBCADTEF Operon Confers Colistin (Hetero)Resistance to Escherichia coliThe use of colistin as a last-resort antimicrobial is compromised by the emergence of resistant enterobacteria with acquired determinants like mcr genes, mutations that activate the PmrAB system, and still unknown mechanisms. This work analyzed 74 Escherichia coli isolates from healthy swine, turkey, or bovine, characterizing their colistin resistance...
Mechanisms of ResistanceMissense Mutations in the CrrB Protein Mediate Odilorhabdin Derivative Resistance in Klebsiella pneumoniaeNOSO-502 is a preclinical antibiotic candidate of the odilorhabdin class. This compound exhibits activity against Enterobacteriaceae pathogens, including carbapenemase-producing bacteria and most of the colistin (CST)-resistant strains.
Mechanisms of ResistanceLytic Bacteriophages Facilitate Antibiotic Sensitization of Enterococcus faeciumEnterococcus faecium, a commensal of the human intestine, has emerged as a hospital-adapted, multidrug-resistant (MDR) pathogen. Bacteriophages (phages), natural predators of bacteria, have regained attention as therapeutics to stem the rise of MDR bacteria.
Mechanisms of ResistanceSpoT-Mediated NapA Upregulation Promotes Oxidative Stress-Induced Helicobacter pylori Biofilm Formation and Confers Multidrug ResistanceRecently, the incidence of drug-resistant Helicobacter pylori infection has increased. Biofilm formation confers multidrug resistance on bacteria.
Mechanisms of ResistanceEmergence of Two AcrB Substitutions Conferring Multidrug Resistance to Salmonella spp.AcrAB-TolC is a major tripartite multidrug efflux pump conferring resistance to a wide variety of compounds in Gram-negative pathogens. Many AcrB mutants have been constructed through site-directed mutagenesis to probe the mechanism of AcrB function in antibiotic resistance.
Mechanisms of ResistanceAzole Resistance Mechanisms in Pathogenic Malassezia furfurMalassezia spp. are emerging fungal pathogens causing opportunistic skin and severe systemic infection. Nosocomial outbreaks are associated with azole resistance, and understanding of the underlying mechanisms is limited to knowledge of other fungal species.
Mechanisms of ResistanceAnalysis of the Contribution of cyp51 Genes to Azole Resistance in Aspergillus Section Nigri with the CRISPR-Cas9 TechniqueCyp51 contribution to azole resistance has been broadly studied and characterized in Aspergillus fumigatus, whereas it remains poorly investigated in other clinically relevant species of the genus, such as those of section Nigri. In this work, we aimed to analyze the impact of cyp51 genes (cyp51A and cyp51B) on the voriconazole (VRC...
Mechanisms of ResistanceIdentification and Characterization of Two Novel ISCR1-Associated Genes, dfrA42 and dfrA43, Encoding Trimethoprim-Resistant Dihydrofolate ReductasesTwo novel ISCR1-associated dfr genes, dfrA42 and dfrA43, were identified from trimethoprim (TMP)-resistant Proteus strains and were shown to confer high levels of TMP resistance (MIC, ≥1,024 mg/liter) when cloned into Escherichia coli isolates. These genes were hosted by complex class 1 integrons, suggesting their potential...
Mechanisms of ResistanceClinical Relevance of Topical Antibiotic Use in Coselecting for Multidrug-Resistant Staphylococcus aureus: Insights from In Vitro and Ex Vivo ModelsTopical antibiotic preparations, such as fusidic acid (FA) or mupirocin, are used in the prevention and treatment of superficial skin infections caused by staphylococci. Previous genomic epidemiology work has suggested an association between the widespread use of topical antibiotics and the emergence of methicillin-resistant Staphylococcus aureus in some settings....
Mechanisms of ResistanceDeletion of Rv2571c Confers Resistance to Arylamide Compounds in Mycobacterium tuberculosis...Tuberculosis, caused by Mycobacterium tuberculosis, is an urgent global health problem requiring new drugs, new drug targets, and an increased understanding of antibiotic resistance. We have determined the mode of resistance to be a series of arylamide compounds in M. tuberculosis.
Mechanisms of ResistanceIntegrative and Conjugative Element-Mediated Azithromycin Resistance in Multidrug-Resistant Salmonella enterica Serovar AlbanyWe identified an erm42-carrying integrative and conjugative element, ICE_erm42, in 26.4% of multidrug-resistant Salmonella enterica serovar Albany isolates recovered from cases of human salmonellosis between 2014 and 2019 in Taiwan. ICE_erm42-carrying strains displayed high-level resistance to azithromycin, and the element could move into the phylogenetically...
Mechanisms of ResistanceNovel ERG11 and TAC1b Mutations Associated with Azole Resistance in Candida aurisCandida auris is a novel Candida species that has spread in all continents, causing nosocomial outbreaks of invasive candidiasis. C. auris has the ability to develop resistance to all antifungal drug classes. Notably, many C....
Susceptibility
SusceptibilityDrug Susceptibility Distributions of Mycobacterium chimaera and Other Nontuberculous MycobacteriaRecent outbreaks of cardiac surgery-associated Mycobacterium chimaera infections have highlighted the importance of species differentiation within the Mycobacterium avium complex and pointed to a lack of antibiotic susceptibility data for M. chimaera. Using the MGIT 960/EpiCenter TB eXiST...
SusceptibilityAntibiotic Susceptibility of Clinical Burkholderia pseudomallei Isolates in Northeast Thailand from 2015 to 2018 and the Genomic Characterization of β-Lactam-Resistant IsolatesMelioidosis is an often fatal infection in tropical regions caused by an environmental bacterium, Burkholderia pseudomallei. Current recommended melioidosis treatment requires intravenous β-lactam antibiotics such as ceftazidime (CAZ), meropenem (MEM), or amoxicillin-clavulanic acid (AMC) and oral trimethoprim-sulfamethoxazole.
SusceptibilityEfficacy and Safety of Oral Fosfomycin for Asymptomatic Bacteriuria in Kidney Transplant Recipients: Results from a Spanish Multicenter CohortCurrent guidelines recommend against systematic screening for or treating asymptomatic bacteriuria (AB) among kidney transplant (KT) recipients, although the evidence regarding episodes occurring early after transplantation or in the presence of anatomical abnormalities is inconclusive. Oral fosfomycin may constitute a good option for the treatment of posttransplant AB, particularly due to the emergence of multidrug-resistant (MDR)...
SusceptibilityIn Vitro Susceptibility of Plasmodium falciparum Isolates from the China-Myanmar Border Area to Piperaquine and Association with Candidate MarkersPlasmodium falciparum from the Greater Mekong subregion has evolved resistance to the artemisinin-based combination therapy dihydroartemisinin and the partner drug piperaquine. To monitor the potential westward spread or independent evolution of piperaquine resistance, we evaluated the in vitro susceptibility of 120...
SusceptibilityAntimicrobial Resistance in Clinical Isolates of Ureaplasma spp. from Samples in GermanyUreaplasma urealyticum and Ureaplasma parvum are mollicutes species that colonize the urogenital tract of many asymptomatic people but are also thought to be associated with symptomatic infections. Using 170 strains isolated between 2016 and 2019 in a German university hospital, resistance was...
SusceptibilityPotency of Olorofim (F901318) Compared to Contemporary Antifungal Agents against Clinical Aspergillus fumigatus Isolates and Review of Azole Resistance Phenotype and Genotype Epidemiology in ChinaTriazole resistance in Aspergillus fumigatus is an increasing worldwide problem that causes major challenges in the management of aspergillosis. New antifungal drugs are needed, with novel targets, that are effective in triazole-resistant infection.
SusceptibilityDeveloping Synergistic Drug Combinations To Restore Antibiotic Sensitivity in Drug-Resistant Mycobacterium tuberculosisTuberculosis (TB) is a leading global cause of mortality owing to an infectious agent, accounting for almost one-third of antimicrobial resistance (AMR) deaths annually. We aimed to identify synergistic anti-TB drug combinations with the capacity to restore therapeutic efficacy against drug-resistant mutants of the causative agent, Mycobacterium tuberculosis.
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SusceptibilityIn Vitro Activity of Rifamycin Derivatives against Nontuberculous Mycobacteria, Including Macrolide- and Amikacin-Resistant Clinical IsolatesWe evaluated the in vitro activity of rifamycin derivatives, including rifampin, rifapentine, rifaximin, and rifabutin, against clinical nontuberculous mycobacteria (NTM) isolates. Of the rifamycin derivatives, rifabutin showed the lowest MICs against all NTM species, including Mycobacterium avium complex,...
SusceptibilityImpact of Bicarbonate on PBP2a Production, Maturation, and Functionality in Methicillin-Resistant Staphylococcus aureusCertain methicillin-resistant Staphylococcus aureus (MRSA) strains exhibit β-lactam susceptibility in vitro, ex vivo, and in vivo in the presence of NaHCO3 (NaHCO3-responsive MRSA). Here, we investigate the impact of NaHCO3 on factors required for PBP2a functionality.
SusceptibilityEvaluation of the Performance of Manual Antimicrobial Susceptibility Testing Methods and Disk Breakpoints for Stenotrophomonas maltophiliaStenotrophomonas maltophilia is an emerging cause of serious infections with high associated mortality in immunocompromised patients. Treatment of S. maltophilia infections is complicated by intrinsic resistance to many antimicrobials, including carbapenems, aminoglycosides, and some cephalosporins...
Analytical Procedures
Analytical ProceduresEvaluation of the MAST PAcE Colorimetric Test for Rapid Detection of Carbapenemase Activity in Gram-Negative BacilliThe MAST Carba PAcE test is a colorimetric test used to detect carbapenemase-producing Gram-negative bacilli from cultured colonies. The performances of this test were compared with those of β-CARBA, Carba NP, and RAPIDEC Carba NP tests using a collection of 280 characterized isolates.
Antiviral Agents
Antiviral AgentsGS-9822, a Preclinical LEDGIN Candidate, Displays a Block-and-Lock Phenotype in Cell CultureThe ability of HIV to integrate into the host genome and establish latent reservoirs is the main hurdle preventing an HIV cure. LEDGINs are small-molecule integrase inhibitors that target the binding pocket of LEDGF/p75, a cellular cofactor that substantially contributes to HIV integration site selection.
Antiviral AgentsLong Dissociation of Bictegravir from HIV-1 Integrase-DNA ComplexesThe HIV integrase (IN) strand transfer inhibitor (INSTI) bictegravir (BIC) has a long dissociation half-life (t1/2) from wild-type IN-DNA complexes: BIC 163 h > dolutegravir (DTG) 96 h > raltegravir (RAL) 10 h > elvitegravir (EVG) 3.3 h. In cells, BIC had more durable antiviral activity against wild-type HIV after drug washout than RAL or EVG.
Antiviral AgentsHuman Safety, Tolerability, and Pharmacokinetics of Molnupiravir, a Novel Broad-Spectrum Oral Antiviral Agent with Activity against SARS-CoV-2Molnupiravir (EIDD-2801/MK-4482), the prodrug of the active antiviral ribonucleoside analog β-d-N4-hydroxycytidine (NHC; EIDD-1931), has activity against a number of RNA viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and seasonal and pandemic influenza viruses....
Epidemiology and Surveillance
Epidemiology and SurveillanceConsecutive Antibiotic Shortages Highlight Discrepancies between Microbiology and Prescribing Practices for Intra-abdominal InfectionsPiperacillin-tazobactam (TZP) is frequently used for intra-abdominal infection (IAI). Our institution experienced consecutive shortages of TZP and cefepime, providing an opportunity to review prescribing patterns and microbiology for IAI.
Epidemiology and SurveillanceHospital Outbreak of Fluconazole-Resistant Candida parapsilosis: Arguments for Clonal Transmission and Long-Term PersistenceThe worldwide emergence of multidrug-resistant pathogenic fungi is a threat to human health. At this very moment, an emergence of Candida parapsilosis isolates harboring a resistance to fluconazole, one of the most popular antifungal drugs, is being described in several countries.
Epidemiology and SurveillanceTyping of Neisseria gonorrhoeae Isolates in Shenzhen, China, from 2014 to 2018 Reveals the Shift of Genotypes Significantly Associated with Antimicrobial ResistanceThe growing antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a serious global threat to gonococcal therapy. Molecular typing is an ideal tool to reveal the association between specific genotypes and resistance phenotypes that provide effective data for tracking the transmission of resistant clones of...
Epidemiology and SurveillanceHorsing Around: Escherichia coli ST1250 of Equine Origin Harboring Epidemic IncHI1/ST9 Plasmid with blaCTX-M-1 and an Operon for Short-Chain Fructooligosaccharide MetabolismThe relatedness of the equine-associated Escherichia coli strain ST1250 and its single- and double-locus variants (ST1250-SLV/DLV), obtained from horses in Europe, was studied by comparative genome analysis. A total of 54 isolates of E. coli ST1250 and ST1250-SLV/DLV from healthy and hospitalized...
Epidemiology and SurveillanceDesign of Proxy Indicators Estimating the Appropriateness of Antibiotics Prescribed by French Dentists: a Cross-Sectional Study Based on Reimbursement DataThe literature shows that the prescription of antibiotics in dental care is often unnecessary or inappropriate. Indicators estimating the appropriateness of antibiotics prescribed by dentists based on routine databases are, however, not available in the literature.
Experimental Therapeutics
Experimental TherapeuticsOmadacycline Compared to Vancomycin When Combined with Germinants To Disrupt the Life Cycle of Clostridioides difficileClostridioides difficile infections (CDI) are commonly treated with antibiotics that do not impact the dormant spore form of the pathogen. CDI-directed antibiotics, such as vancomycin and metronidazole, can destroy the vegetative form of C. difficile and protective microbiota.
Experimental TherapeuticsIn Vitro Antibacterial Activity of Hydrogen Peroxide and Hypochlorous Acid, Including That Generated by Electrochemical ScaffoldsHydrogen peroxide (H2O2) and hypochlorous acid (HOCl) are biocides used for cleaning and debriding chronic wound infections, which often harbor drug-resistant bacteria. Here, we evaluated the in vitro activity of H2O2 and HOCl against 27 isolates of eight bacterial species involved in wound infections.
Experimental TherapeuticsAmine-Linked Flavonoids as Agents against Cutaneous LeishmaniasisWe have designed, synthesized, and characterized a library of 38 novel flavonoid compounds linked with amines. Some of these amine-linked flavonoids have potent in vitro activity against parasites that cause cutaneous leishmaniasis, a tropical disease endemic in 80 countries worldwide.
Experimental TherapeuticsTargeting Superoxide Dismutase Confers Enhanced Reactive Oxygen Species-Mediated Eradication of Polymyxin B-Induced Acinetobacter baumannii PersistersBacterial persisters represent noninheritable drug-tolerant populations that are linked to recalcitrance of infections in health care settings. The rise of antibiotic resistance and the depletion of new antibiotics in the drug discovery pipeline have made the task of persister eradication more daunting.
Experimental TherapeuticsTherapeutic Potential of Coumestan Pks13 Inhibitors for TuberculosisPolyketide synthase 13 (Pks13) is an important enzyme found in Mycobacterium tuberculosis that condenses two fatty acyl chains to produce α-alkyl β-ketoesters, which in turn serve as the precursors for the synthesis of mycolic acids that are essential building blocks for maintaining the cell wall integrity of...
Experimental TherapeuticsActivity of Fosfomycin and Amikacin against Fosfomycin-Heteroresistant Escherichia coli Strains in a Hollow-Fiber Infection ModelWe evaluated human-like the efficacy of intravenous doses of fosfomycin of 8 g every 8 h (8 g/Q8h) and of amikacin (15 mg/kg/Q24h) in monotherapy and in combination against six fosfomycin-heteroresistant Escherichia coli isolates using a hollow-fiber infection model (HFIM). Six fosfomycin-heteroresistant E...
Experimental TherapeuticsA Novel Transdermal Application for Clearing Skin Colonization by Candida aurisCandida auris has demonstrated the ability to colonize the skin of hospitalized patients, possibly contributing to nosocomial spread. The objective of this study was to determine whether two novel transdermal agents could clear skin colonization established by C. auris.
Experimental TherapeuticsIn Vitro and In Vivo Characterization of Tebipenem, an Orally Active Carbapenem, against Biothreat PathogensBacillus anthracis and Yersinia pestis, the causative pathogens for anthrax and plague, respectively, along with Burkholderia mallei and Burkholderia pseudomallei...
Experimental TherapeuticsA Leucyl-tRNA Synthetase Inhibitor with Broad-Spectrum Antimycobacterial ActivityGlobal infections by nontuberculous mycobacteria (NTM) are steadily rising. New drugs are needed to treat NTM infections, but the NTM drug pipeline remains poorly populated and focused on repurposing or reformulating approved antibiotics.
Experimental TherapeuticsAntifungal Activity of Acylhydrazone Derivatives against Sporothrix spp.Sporotrichosis is an emerging mycosis caused by members of the genus Sporothrix. The disease affects humans and animals, particularly cats, which play an important role in zoonotic transmission.
Experimental TherapeuticsEffect of Itraconazole-Ezetimibe-Miltefosine Ternary Therapy in Murine Visceral LeishmaniasisDrug combination therapy is an interesting approach to increase the success of drug repurposing for neglected diseases. Thus, the objective of this work was to evaluate binary and ternary therapies composed of itraconazole, ezetimibe, and miltefosine for the treatment of visceral leishmaniasis.
Clinical Therapeutics
Clinical TherapeuticsA Physiologically Based Pharmacokinetic Analysis To Predict the Pharmacokinetics of Intravenous Isavuconazole in Patients with or without Hepatic ImpairmentIsavuconazole (ISA) is an azole antifungal used in the treatment of invasive aspergillosis and mucormycosis. Patients with mild or moderate hepatic impairment have lower clearance (CL) than the healthy population.
Clinical TherapeuticsPopulation Pharmacokinetics and Monte Carlo Simulation for Dosage Optimization of Fosfomycin in the Treatment of Osteoarticular Infections in Patients without Renal DysfunctionFosfomycin is gaining interest in the treatment of complex osteoarticular infections (OI) due to multidrug-resistant (MDR) pathogens. Our aims were to conduct population pharmacokinetics of fosfomycin in a cohort of OI patients receiving 16 g daily by intermittent (II) or continuous (CI) infusion and to carry out Monte Carlo simulations for dosage optimization in the treatment of these infections.
Clinical TherapeuticsPopulation Pharmacokinetics of Dalbavancin and Dosing Consideration for Optimal Treatment of Adult Patients with Staphylococcal Osteoarticular InfectionsDalbavancin is gaining interest in the treatment of complex osteoarticular (OA) infections. We aimed to conduct a population pharmacokinetic analysis of dalbavancin in a prospective cohort of adult patients with OA infections caused by Gram-positive organisms and to identify optimal dosing regimens for long-term treatment.
Pharmacology
PharmacologyNovel Short-Course Therapy and Morphism Mapping for Clinical Pulmonary Mycobacterium kansasiiStandard therapy (isoniazid, rifampin, and ethambutol), with or without a macrolide, for pulmonary Mycobacterium kansasii lasts more than a year. Therefore, shorter treatment duration regimens are required.
PharmacologySynchrotron-Based X-Ray Fluorescence Microscopy Reveals Accumulation of Polymyxins in Single Human Alveolar Epithelial CellsIntravenous administration of the last-line polymyxins results in poor drug exposure in the lungs and potential nephrotoxicity, whereas inhalation therapy offers better pharmacokinetics/pharmacodynamics for pulmonary infections by delivering the antibiotic directly to the infection site. However, polymyxin inhalation therapy has not been optimized, and adverse effects can occur.
PharmacologySemimechanistic Pharmacokinetic/Pharmacodynamic Modeling of Fosfomycin and Sulbactam Combination against Carbapenem-Resistant Acinetobacter baumanniiDue to limited treatment options for carbapenem-resistant Acinetobacter baumannii (CR-AB) infections, antibiotic combinations are now considered potential treatments for CR-AB. This study aimed to explore the utility of fosfomycin-sulbactam combination (FOS/SUL) therapy against CR-AB isolates.
PharmacologyPopulation Pharmacokinetics and Dosage Optimization of Linezolid in Critically Ill Pediatric PatientsLinezolid is an oxazolidinone antibiotic exhibiting efficacy against multidrug-resistant (MDR) Gram-positive-related infections. However, its population pharmacokinetic (PopPK) profile in critically ill Chinese children has not been characterized.
PharmacologyPhase 1 Study of the Safety, Tolerability, and Pharmacokinetics of Biapenem in Healthy Adult SubjectsThe pharmacokinetics and safety of biapenem were studied in 36 healthy adult subjects in a randomized, placebo-controlled, double blind, sequential single- and multiple-ascending-dose study using doses from 250 to 1,250 mg administered three times a day using 3-h infusions. Maximum concentrations for biapenem were achieved at the end of the 3-h infusion.
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