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Expert Opinion on Therapeutic Patents 2023β-Lactams, which include monobactams, remain the most important class of antibiotics worldwide. Aztreonam, the only monobactam in clinical use, has remarkable activity... (Review)
Review
INTRODUCTION
β-Lactams, which include monobactams, remain the most important class of antibiotics worldwide. Aztreonam, the only monobactam in clinical use, has remarkable activity against many Gram-negative bacteria, but limited activity against some of the most problematic multidrug-resistant (MDR) pathogens, such as MDR and co-expressing extended-spectrum- and metallo-β-lactamases, which can inactivate aztreonam by hydrolysis.
AREAS COVERED
Structurally novel siderophore-conjugated aztreonam derivatives with improved antibacterial properties against several high-priority pathogens are claimed. This invention reports that sidechain extension of aztreonam is tolerated; the coupling of its aminothiazoloxime carboxylic acid part with a siderophore mimetic significantly improved the antibacterial activity against several problematic strains, including MDR isolates with carbapenemase/cephalosporinase activity.
EXPERT OPINION
Finding new strategies to tackle bacterial resistance to β-lactam antibiotics is critical. Considering that β lactams are validated and safe drugs, this research may stimulate the field to develop new ideas in the arena of antimicrobial drug discovery, particularly with respect to siderophore mimetics.
Topics: Humans; Monobactams; Aztreonam; Siderophores; Patents as Topic; Anti-Bacterial Agents; beta-Lactams; beta-Lactamases; Microbial Sensitivity Tests
PubMed: 37902072
DOI: 10.1080/13543776.2023.2262135 -
The Pediatric Infectious Disease Journal Sep 1989Monocyclic beta-lactam antibiotics (monobactams) are structurally unique from the traditional bicyclic beta-lactams because of their single ring configuration.... (Review)
Review
Monocyclic beta-lactam antibiotics (monobactams) are structurally unique from the traditional bicyclic beta-lactams because of their single ring configuration. Aztreonam, the first of these monobactams, has been studied extensively in order to determine its pharmacologic and pharmacokinetic profile in adults and children with bacterial infections. It has been established, for example, that with intramuscular or intravenous dosing (30 to 50 mg/kg in children and 1 to 2 g in adults), serum concentrations above the minimum inhibitory concentrations of most aerobic Gram-negative bacteria can be maintained for up to 8 hours. Against a less susceptible pathogen such as Pseudomonas aeruginosa, every-6-hour dosing allows for preservation of the bactericidal effect, although longer intervals may be practical in low birth weight infants. The drug is primarily (80%) excreted by renal mechanisms and serum clearance varies with postnatal age. Distribution into body fluids is similar to that of other beta-lactams. For example in the presence of meningeal inflammation, cerebrospinal fluid concentrations are 17 to 33% of serum values. Urinary concentrations are high and prolonged with greater than 80% appearing as the active drug. Preliminary data from cystic fibrosis patients suggest that there are very minor pharmacokinetic differences in this population. The pharmacologic profile indicates that aztreonam may provide an appropriate alternative to traditional therapy for serious Gram-negative aerobic infections in infants and children.
Topics: Age Factors; Aztreonam; Humans; Injections, Intramuscular; Injections, Intravenous; Tissue Distribution
PubMed: 2682507
DOI: No ID Found -
Journal of Chemotherapy (Florence,... Jul 1989
Topics: Anti-Bacterial Agents; Bacteria, Aerobic; Drug Synergism; Drug Therapy, Combination; Escherichia coli; Gram-Negative Bacteria; Monobactams; Staphylococcus aureus
PubMed: 16312336
DOI: No ID Found -
Expert Review of Anti-infective Therapy Oct 2011The spread of resistance among Gram-positive and Gram-negative bacteria represents a growing challenge for the development of new antimicrobials. The pace of antibiotic... (Review)
Review
The spread of resistance among Gram-positive and Gram-negative bacteria represents a growing challenge for the development of new antimicrobials. The pace of antibiotic drug development has slowed during the last decade and, especially for Gram-negatives, clinicians are facing a dramatic shortage in the availability of therapeutic options to face the emergency of the resistance problem throughout the world. In this alarming scenario, although there is a shortage of compounds reaching the market in the near future, antibiotic discovery remains one of the keys to successfully stem and maybe overcome the tide of resistance. Analogs of already known compounds and new agents belonging to completely new classes of antimicrobials are in early stages of development. Novel and promising anti-Gram-negative antimicrobials belong both to old (cephalosporins, carbapenems, β-lactamase inhibitors, monobactams, aminoglycosides, polymyxin analogues and tetracycline) and completely new antibacterial classes (boron-containing antibacterial protein synthesis inhibitors, bis-indoles, outer membrane synthesis inhibitors, antibiotics targeting novel sites of the 50S ribosomal subunit and antimicrobial peptides). However, all of these compounds are still far from being introduced into clinical practice. Therefore, infection control policies and optimization in the use of already existing molecules are still the most effective approaches to reduce the spread of resistance and preserve the activity of antimicrobials.
Topics: Aminoglycosides; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Carbapenems; Clinical Trials as Topic; Drug Administration Schedule; Drug Discovery; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Indoles; Infection Control; Microbial Sensitivity Tests; Monobactams; Polymyxins; Protein Synthesis Inhibitors; beta-Lactamases
PubMed: 21973303
DOI: 10.1586/eri.11.107 -
Pharmacology & Therapeutics 1985
Review
Topics: Anti-Bacterial Agents; Bacteria; Cephalosporins; Cephamycins; Gram-Negative Aerobic Bacteria; Gram-Negative Anaerobic Bacteria; Gram-Positive Bacteria; Humans; Kinetics; Monobactams; Penicillins; Thienamycins; beta-Lactamase Inhibitors
PubMed: 3915359
DOI: 10.1016/0163-7258(85)90007-5 -
The American Journal of the Medical... Jul 1991Aztreonam represents the first synthetic monobactam marketed in the United States and is being viewed as a nontoxic alternative to the aminoglycosides. Advantages of... (Review)
Review
Aztreonam represents the first synthetic monobactam marketed in the United States and is being viewed as a nontoxic alternative to the aminoglycosides. Advantages of aztreonam over the aminoglycosides include lack of ototoxicity and nephrotoxicity and better penetration into the CSF. Additional advantages include its use in penicillin and cephalosporin allergic patients. Disadvantages of aztreonam compared to the aminoglycosides include the cost of the drug (50 times more expensive than gentamicin), the lack of post antibiotic effect, resistance to P. aeruginosa, and lack of significant activity against Enterobacter cloacae and E. aerogenes. There are insufficient clinical trials to document the superiority of aztreonam over the "gold standard" therapy for gram-negative infections--the aminoglycosides. The restricted anti-microbial spectrum of aztreonam has been proposed as an advantage. Theoretically, this would permit targeting of a gram-negative pathogen with minimal disruption of the (largely anaerobic) intestinal flora. In fact, use of this drug has been associated with colonization of gram-positive organism, especially enterococci. Although aztreonam appears to be an excellent antibiotic, its use has been limited by its relatively high cost, narrow spectrum of activity, and the availability of numerous alternative agents.
Topics: Aztreonam; Humans; Microbial Sensitivity Tests
PubMed: 2063887
DOI: 10.1097/00000441-199107000-00011 -
Tidsskrift For Den Norske Laegeforening... Dec 2008beta-lactams are our most valuable and frequently used antibiotics. Resistance towards them, in both Gram-positive and Gram-negative bacteria, challenges their... (Review)
Review
BACKGROUND
beta-lactams are our most valuable and frequently used antibiotics. Resistance towards them, in both Gram-positive and Gram-negative bacteria, challenges their antimicrobial effect. beta-lactamases are the most important resistance mechanism against beta-lactams in Gram-negative bacteria.
MATERIAL AND METHODS
This review is based on literature retrieved through a non-systematic search of Pubmed (with the terms "ESBL", "AmpC", and "carbapenemases"), as well as the authors' own research experience.
RESULTS AND INTERPRETATION
We now observe a global dissemination of particularly broad spectrum beta-lactamases; extended-spectrum beta-lactamases (ESBLs), plasmid-mediated AmpC, and carbapenemases. These beta-lactamases are hosted by multidrug-resistant clones of Enterobacteriaceae, Pseudomonas aeruginosa with few, if any, therapeutic alternatives. We have observed that this pandemic has reached Norway with an increase in ESBL-producing Escherichia coli in particular, but also pan-resistant carbapenemase-producing K. pneumoniae, P. aeruginosa OG A. baumannii during the last years. The latter ones have been associated with import after hospitalization abroad, but this situation may change due to the epidemic potential of these resistant clones. Rapid diagnostic service and targeted infection control measures are important to prevent them from spreading.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Carbapenems; Cephalosporins; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Monobactams; Penicillins; Plasmids; beta-Lactam Resistance; beta-Lactamases; beta-Lactams
PubMed: 19079424
DOI: No ID Found -
MBio Feb 2023The purine-derived signaling molecules c-di-AMP and (p)ppGpp control /PBP2a-mediated β-lactam resistance in methicillin-resistant Staphylococcus aureus (MRSA) raise the...
The purine-derived signaling molecules c-di-AMP and (p)ppGpp control /PBP2a-mediated β-lactam resistance in methicillin-resistant Staphylococcus aureus (MRSA) raise the possibility that purine availability can control antibiotic susceptibility. Consistent with this, exogenous guanosine and xanthosine, which are fluxed through the GTP branch of purine biosynthesis, were shown to significantly reduce MRSA β-lactam resistance. In contrast, adenosine (fluxed to ATP) significantly increased oxacillin resistance, whereas inosine (which can be fluxed to ATP and GTP via hypoxanthine) only marginally increased oxacillin susceptibility. Furthermore, mutations that interfere with purine synthesis ( operon), transport (NupG, PbuG, PbuX) and the salvage pathway (DeoD2, Hpt) increased β-lactam resistance in MRSA strain JE2. Increased resistance of a mutant was not significantly reversed by guanosine, indicating that NupG is required for guanosine transport, which is required to reduce β-lactam resistance. Suppressor mutants resistant to oxacillin/guanosine combinations contained several purine salvage pathway mutations, including and . Guanosine significantly increased cell size and reduced levels of c-di-AMP, while inactivation of GdpP, the c-di-AMP phosphodiesterase negated the impact of guanosine on β-lactam susceptibility. PBP2a expression was unaffected in or mutants, suggesting that guanosine-induced β-lactam susceptibility may result from dysfunctional c-di-AMP-dependent osmoregulation. These data reveal the therapeutic potential of purine nucleosides, as β-lactam adjuvants that interfere with the normal activation of c-di-AMP are required for high-level β-lactam resistance in MRSA. The clinical burden of infections caused by antimicrobial resistant (AMR) pathogens is a leading threat to public health. Maintaining the effectiveness of existing antimicrobial drugs or finding ways to reintroduce drugs to which resistance is widespread is an important part of efforts to address the AMR crisis. Predominantly, the safest and most effective class of antibiotics are the β-lactams, which are no longer effective against methicillin-resistant Staphylococcus aureus (MRSA). Here, we report that the purine nucleosides guanosine and xanthosine have potent activity as adjuvants that can resensitize MRSA to oxacillin and other β-lactam antibiotics. Mechanistically, exposure of MRSA to these nucleosides significantly reduced the levels of the cyclic dinucleotide c-di-AMP, which is required for β-lactam resistance. Drugs derived from nucleotides are widely used in the treatment of cancer and viral infections highlighting the clinical potential of using purine nucleosides to restore or enhance the therapeutic effectiveness of β-lactams against MRSA and potentially other AMR pathogens.
Topics: Methicillin-Resistant Staphylococcus aureus; Purine Nucleosides; Bacterial Proteins; Anti-Bacterial Agents; Oxacillin; beta-Lactams; Monobactams; Guanosine; Adenosine Triphosphate; Guanosine Triphosphate; Microbial Sensitivity Tests; Penicillin-Binding Proteins; beta-Lactam Resistance
PubMed: 36507833
DOI: 10.1128/mbio.02478-22 -
Anasthesiologie, Intensivmedizin,... Apr 2023
Topics: Humans; Penicillins; Anti-Bacterial Agents; Hypersensitivity; Monobactams; Drug Hypersensitivity
PubMed: 37044110
DOI: 10.1055/a-1933-2408 -
The Journal of Antibiotics Mar 2024Cephalosporins comprise a β-lactam antibiotic class whose first members were discovered in 1945 from the fungus Cephalosporium acremonium. Their clinical use for... (Review)
Review
Cephalosporins comprise a β-lactam antibiotic class whose first members were discovered in 1945 from the fungus Cephalosporium acremonium. Their clinical use for Gram-negative bacterial infections is widespread due to their ability to traverse outer membranes through porins to gain access to the periplasm and disrupt peptidoglycan synthesis. More recent members of the cephalosporin class are administered as last resort treatments for complicated urinary tract infections, MRSA, and other multi-drug resistant pathogens, such as Neisseria gonorrhoeae. Unfortunately, there has been a global increase in cephalosporin-resistant strains, heteroresistance to this drug class has been a topic of increasing concern, and tolerance and persistence are recognized as potential causes of cephalosporin treatment failure. In this review, we summarize the cephalosporin antibiotic class from discovery to their mechanisms of action, and discuss the causes of cephalosporin treatment failure, which include resistance, tolerance, and phenomena when those qualities are exhibited by only small subpopulations of bacterial cultures (heteroresistance and persistence). Further, we discuss how recent efforts with cephalosporin conjugates and combination treatments aim to reinvigorate this antibiotic class.
Topics: Humans; Cephalosporin Resistance; Anti-Bacterial Agents; Cephalosporins; Gram-Negative Bacterial Infections; Neisseria gonorrhoeae; Monobactams
PubMed: 38114565
DOI: 10.1038/s41429-023-00687-y