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1.
Drugs ; 82(5): 533-557, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1827389

ABSTRACT

Sulopenem (formerly known as CP-70,429, and CP-65,207 when a component of a racemic mixture with its R isomer) is an intravenous and oral penem that possesses in vitro activity against fluoroquinolone-resistant, extended spectrum ß-lactamases (ESBL)-producing, multidrug-resistant (MDR) Enterobacterales. Sulopenem is being developed to treat patients with uncomplicated and complicated urinary tract infections (UTIs) as well as intra-abdominal infections. This review will focus mainly on its use in UTIs. The chemical structure of sulopenem shares properties of penicillins, cephalosporins, and carbapenems. Sulopenem is available as an oral prodrug formulation, sulopenem etzadroxil, which is hydrolyzed by intestinal esterases, resulting in active sulopenem. In early studies, the S isomer of CP-65,207, later developed as sulopenem, demonstrated greater absorption, higher drug concentrations in the urine, and increased stability against the renal enzyme dehydropeptidase-1 compared with the R isomer, which set the stage for its further development as a UTI antimicrobial. Sulopenem is active against both Gram-negative and Gram-positive microorganisms. Sulopenem's ß-lactam ring alkylates the serine residues of penicillin-binding protein (PBP), which inhibits peptidoglycan cross-linking. Due to its ionization and low molecular weight, sulopenem passes through outer membrane proteins to reach PBPs of Gram-negative bacteria. While sulopenem activity is unaffected by many ß-lactamases, resistance arises from alterations in PBPs (e.g., methicillin-resistant Staphylococcus aureus [MRSA]), expression of carbapenemases (e.g., carbapenemase-producing Enterobacterales and in Stenotrophomonas maltophilia), reduction in the expression of outer membrane proteins (e.g., some Klebsiella spp.), and the presence of efflux pumps (e.g., MexAB-OprM in Pseudomonas aeruginosa), or a combination of these mechanisms. In vitro studies have reported that sulopenem demonstrates greater activity than meropenem and ertapenem against Enterococcus faecalis, Listeria monocytogenes, methicillin-susceptible S. aureus (MSSA), and Staphylococcus epidermidis, as well as similar activity to carbapenems against Streptococcus agalactiae, Streptococcus pneumoniae, and Streptococcus pyogenes. With some exceptions, sulopenem activity against Gram-negative aerobes was less than ertapenem and meropenem but greater than imipenem. Sulopenem activity against Escherichia coli carrying ESBL, CTX-M, or Amp-C enzymes, or demonstrating MDR phenotypes, as well as against ESBL-producing Klebsiella pneumoniae, was nearly identical to ertapenem and meropenem and greater than imipenem. Sulopenem exhibited identical or slightly greater activity than imipenem against many Gram-positive and Gram-negative anaerobes, including Bacteroides fragilis. The pharmacokinetics of intravenous sulopenem appear similar to carbapenems such as imipenem-cilastatin, meropenem, and doripenem. In healthy subjects, reported volumes of distribution (Vd) ranged from 15.8 to 27.6 L, total drug clearances (CLT) of 18.9-24.9 L/h, protein binding of approximately 10%, and elimination half-lives (t½) of 0.88-1.03 h. The estimated renal clearance (CLR) of sulopenem is 8.0-10.6 L/h, with 35.5% ± 6.7% of a 1000 mg dose recovered unchanged in the urine. An ester prodrug, sulopenem etzadroxil, has been developed for oral administration. Initial investigations reported a variable oral bioavailability of 20-34% under fasted conditions, however subsequent work showed that bioavailability is significantly improved by administering sulopenem with food to increase its oral absorption or with probenecid to reduce its renal tubular secretion. Food consumption increases the area under the curve (AUC) of oral sulopenem (500 mg twice daily) by 23.6% when administered alone and 62% when administered with 500 mg of probenecid. Like carbapenems, sulopenem demonstrates bactericidal activity that is associated with the percentage of time that free concentrations exceed the MIC (%f T > MIC). In animal models, bacteriostasis was associated with %f T > MICs ranging from 8.6 to 17%, whereas 2-log10 kill was seen at values ranging from 12 to 28%. No pharmacodynamic targets have been documented for suppression of resistance. Sulopenem concentrations in urine are variable, ranging from 21.8 to 420.0 mg/L (median 84.4 mg/L) in fasted subjects and 28.8 to 609.0 mg/L (median 87.3 mg/L) in those who were fed. Sulopenem has been compared with carbapenems and cephalosporins in guinea pig and murine systemic and lung infection animal models. Studied pathogens included Acinetobacter calcoaceticus, B. fragilis, Citrobacter freundii, Enterobacter cloacae, E. coli, K. pneumoniae, Proteus vulgaris, and Serratia marcescens. These studies reported that overall, sulopenem was non-inferior to carbapenems but appeared to be superior to cephalosporins. A phase III clinical trial (SURE-1) reported that sulopenem was not non-inferior to ciprofloxacin in women infected with fluoroquinolone-susceptible pathogens, due to a higher rate of asymptomatic bacteriuria in sulopenem-treated patients at the test-of-cure visit. However, the researchers reported superiority of sulopenem etzadroxil/probenecid over ciprofloxacin for the treatment of uncomplicated UTIs in women infected with fluoroquinolone/non-susceptible pathogens, and non-inferiority in all patients with a positive urine culture. A phase III clinical trial (SURE-2) compared intravenous sulopenem followed by oral sulopenem etzadroxil/probenecid with ertapenem in the treatment of complicated UTIs. No difference in overall success was noted at the end of therapy. However, intravenous sulopenem followed by oral sulopenem etzadroxil was not non-inferior to ertapenem followed by oral stepdown therapy in overall success at test-of-cure due to a higher rate of asymptomatic bacteriuria in the sulopenem arm. After a meeting with the US FDA, Iterum stated that they are currently evaluating the optimal design for an additional phase III uncomplicated UTI study to be conducted prior to the potential resubmission of the New Drug Application (NDA). It is unclear at this time whether Iterum intends to apply for EMA or Japanese regulatory approval. The safety and tolerability of sulopenem has been reported in various phase I pharmacokinetic studies and phase III clinical trials. Sulopenem (intravenous and oral) appears to be well tolerated in healthy subjects, with and without the coadministration of probenecid, with few serious drug-related treatment-emergent adverse events (TEAEs) reported to date. Reported TEAEs affecting ≥1% of patients were (from most to least common) diarrhea, nausea, headache, vomiting and dizziness. Discontinuation rates were low and were not different than comparator agents. Sulopenem administered orally and/or intravenously represents a potentially well tolerated and effective option for treating uncomplicated and complicated UTIs, especially in patients with documented or highly suspected antimicrobial pathogens to commonly used agents (e.g. fluoroquinolone-resistant E. coli), and in patients with documented microbiological or clinical failure or patients who demonstrate intolerance/adverse effects to first-line agents. This agent will likely be used orally in the outpatient setting, and intravenously followed by oral stepdown in the hospital setting. Sulopenem also allows for oral stepdown therapy in the hospital setting from intravenous non-sulopenem therapy. More clinical data are required to fully assess the clinical efficacy and safety of sulopenem, especially in patients with complicated UTIs caused by resistant pathogens such as ESBL-producing, Amp-C, MDR E. coli. Antimicrobial stewardship programs will need to create guidelines for when this oral and intravenous penem should be used.


Subject(s)
Bacteriuria , Methicillin-Resistant Staphylococcus aureus , Prodrugs , Urinary Tract Infections , Adenosine Monophosphate/pharmacology , Animals , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Bacteriuria/chemically induced , Bacteriuria/drug therapy , Carbapenems/pharmacology , Cephalosporins/pharmacology , Ciprofloxacin/pharmacology , Ertapenem , Escherichia coli , Female , Fluoroquinolones/pharmacology , Gram-Negative Bacteria , Guinea Pigs , Humans , Imipenem/pharmacology , Lactams , Male , Membrane Proteins/pharmacology , Meropenem/pharmacology , Mice , Probenecid/pharmacology , Prodrugs/pharmacology , Staphylococcus aureus , Urinary Tract Infections/drug therapy , beta-Lactamases/pharmacology
2.
Proc Natl Acad Sci U S A ; 118(26)2021 06 29.
Article in English | MEDLINE | ID: covidwho-1284758

ABSTRACT

Translation of open reading frame 1b (ORF1b) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires a programmed -1 ribosomal frameshift (-1 PRF) promoted by an RNA pseudoknot. The extent to which SARS-CoV-2 replication may be sensitive to changes in -1 PRF efficiency is currently unknown. Through an unbiased, reporter-based high-throughput compound screen, we identified merafloxacin, a fluoroquinolone antibacterial, as a -1 PRF inhibitor for SARS-CoV-2. Frameshift inhibition by merafloxacin is robust to mutations within the pseudoknot region and is similarly effective on -1 PRF of other betacoronaviruses. Consistent with the essential role of -1 PRF in viral gene expression, merafloxacin impedes SARS-CoV-2 replication in Vero E6 cells, thereby providing proof-of-principle for targeting -1 PRF as a plausible and effective antiviral strategy for SARS-CoV-2 and other coronaviruses.


Subject(s)
Antiviral Agents/pharmacology , Frameshifting, Ribosomal/drug effects , SARS-CoV-2/drug effects , Virus Replication/drug effects , Animals , Betacoronavirus , Chlorocebus aethiops , Fluoroquinolones/pharmacology , Frameshifting, Ribosomal/genetics , Mutation , Nucleic Acid Conformation , RNA, Viral/chemistry , RNA, Viral/genetics , SARS-CoV-2/physiology , Vero Cells
3.
Science ; 372(6548): 1306-1313, 2021 06 18.
Article in English | MEDLINE | ID: covidwho-1228853

ABSTRACT

Programmed ribosomal frameshifting is a key event during translation of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA genome that allows synthesis of the viral RNA-dependent RNA polymerase and downstream proteins. Here, we present the cryo-electron microscopy structure of a translating mammalian ribosome primed for frameshifting on the viral RNA. The viral RNA adopts a pseudoknot structure that lodges at the entry to the ribosomal messenger RNA (mRNA) channel to generate tension in the mRNA and promote frameshifting, whereas the nascent viral polyprotein forms distinct interactions with the ribosomal tunnel. Biochemical experiments validate the structural observations and reveal mechanistic and regulatory features that influence frameshifting efficiency. Finally, we compare compounds previously shown to reduce frameshifting with respect to their ability to inhibit SARS-CoV-2 replication, establishing coronavirus frameshifting as a target for antiviral intervention.


Subject(s)
Frameshifting, Ribosomal , RNA, Viral/genetics , Ribosomes/ultrastructure , SARS-CoV-2/genetics , Viral Proteins/biosynthesis , Animals , Antiviral Agents/pharmacology , Codon, Terminator , Coronavirus RNA-Dependent RNA Polymerase/biosynthesis , Coronavirus RNA-Dependent RNA Polymerase/chemistry , Coronavirus RNA-Dependent RNA Polymerase/genetics , Cryoelectron Microscopy , Fluoroquinolones/pharmacology , Frameshifting, Ribosomal/drug effects , Genome, Viral , Humans , Image Processing, Computer-Assisted , Models, Molecular , Nucleic Acid Conformation , Open Reading Frames , Protein Folding , RNA, Messenger/chemistry , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Ribosomal, 18S/chemistry , RNA, Ribosomal, 18S/genetics , RNA, Ribosomal, 18S/metabolism , RNA, Viral/chemistry , RNA, Viral/metabolism , Ribosomal Proteins/metabolism , Ribosomes/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Viral Proteins/chemistry , Viral Proteins/genetics , Virus Replication/drug effects
4.
Viruses ; 13(1)2020 12 23.
Article in English | MEDLINE | ID: covidwho-1044046

ABSTRACT

Repurposing FDA-approved drugs that treat respiratory infections caused by coronaviruses, such as SARS-CoV-2 and MERS-CoV, could quickly provide much needed antiviral therapies. In the current study, the potency and cellular toxicity of four fluoroquinolones (enoxacin, ciprofloxacin, levofloxacin, and moxifloxacin) were assessed in Vero cells and A549 cells engineered to overexpress ACE2, the SARS-CoV-2 entry receptor. All four fluoroquinolones suppressed SARS-CoV-2 replication at high micromolar concentrations in both cell types, with enoxacin demonstrating the lowest effective concentration 50 value (EC50) of 126.4 µM in Vero cells. Enoxacin also suppressed the replication of MERS-CoV-2 in Vero cells at high micromolar concentrations. Cellular toxicity of levofloxacin was not found in either cell type. In Vero cells, minimal toxicity was observed following treatment with ≥37.5 µM enoxacin and 600 µM ciprofloxacin. Toxicity in both cell types was detected after moxifloxacin treatment of ≥300 µM. In summary, these results suggest that the ability of fluoroquinolones to suppress SARS-CoV-2 and MERS-CoV replication in cultured cells is limited.


Subject(s)
Anti-Bacterial Agents/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus Infections/drug therapy , Fluoroquinolones/pharmacology , Middle East Respiratory Syndrome Coronavirus/drug effects , SARS-CoV-2/drug effects , A549 Cells , Angiotensin-Converting Enzyme 2 , Animals , Cell Line , Chlorocebus aethiops , Ciprofloxacin/pharmacology , Enoxacin/pharmacology , Humans , Levofloxacin/pharmacology , Moxifloxacin/pharmacology , Vero Cells
5.
Biomed Res Int ; 2020: 6237160, 2020.
Article in English | MEDLINE | ID: covidwho-868383

ABSTRACT

Coronaviruses have been reported previously due to their association with the severe acute respiratory syndrome (SARS). After SARS, these viruses were known to be causing Middle East respiratory syndrome (MERS) and caused 35% evanescence amid victims pursuing remedial care. Nowadays, beta coronaviruses, members of Coronaviridae, family order Nidovirales, have become subjects of great importance due to their latest pandemic originating from Wuhan, China. The virus named as human-SARS-like coronavirus-2 contains four structural as well as sixteen nonstructural proteins encoded by single-stranded ribonucleic acid of positive polarity. As there is no vaccine available to treat the infection caused by these viruses, there is a dire need for taking necessary steps against this virus. Herein, we have targeted two nonstructural proteins of SARS-CoV-2, namely, methyltransferase (nsp16) and helicase (nsp13), respectively, due to their substantial activity in viral pathogenesis. A total of 2035 compounds were analyzed for their pharmacokinetics and pharmacological properties. The screened 108 compounds were docked against both targeted proteins and were compared with previously reported known compounds. Compounds with high binding affinity were analyzed for their reactivity through DFT analysis, and binding was analyzed using molecular dynamics simulations. Through the analyses performed in this study, it is concluded that EryvarinM, Silydianin, Osajin, and Raddeanine can be considered potential inhibitors for MTase, while TomentodiplaconeB, Osajin, Sesquiterpene Glycoside, Rhamnetin, and Silydianin for helicase after these compounds are validated thoroughly using in vitro and in vivo protocols.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Phytochemicals/chemistry , Phytochemicals/pharmacology , SARS-CoV-2/drug effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/chemistry , Alanine/pharmacology , Antimetabolites/chemistry , Antimetabolites/pharmacology , Antiviral Agents/chemistry , COVID-19/epidemiology , COVID-19/virology , China/epidemiology , Dioxolanes/chemistry , Dioxolanes/pharmacology , Fluoroquinolones/chemistry , Fluoroquinolones/pharmacology , Humans , Methyltransferases/drug effects , Molecular Docking Simulation , Nelfinavir/chemistry , Nelfinavir/pharmacology , Piperazines/chemistry , Piperazines/pharmacology , Protein Conformation , RNA Helicases/drug effects , SARS-CoV-2/chemistry , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Topoisomerase II Inhibitors/chemistry , Topoisomerase II Inhibitors/pharmacology , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism
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