Review

Authors: Karen Bush, Patricia A Bradford

β-Lactams are the most widely used class of antibiotics. Since the discovery of benzylpenicillin in the 1920s, thousands of new penicillin derivatives and related β-lactam classes of cephalosporins, cephamycins, monobactams, and carbapenems have been discovered. Each new class of β-lactam has been developed either to increase the spectrum of activity to include additional bacterial species or to address specific resistance mechanisms that have arisen in the targeted bacterial population. Resistance to β-lactams is primarily because of bacterially produced β-lactamase enzymes that hydrolyze the β-lactam ring, thereby inactivating the drug. The newest effort to circumvent resistance is the development of novel broad-spectrum β-lactamase inhibitors that work against many problematic β-lactamases, including cephalosporinases and serine-based carbapenemases, which severely limit therapeutic options. This work provides a comprehensive overview of β-lactam antibiotics that are currently in use, as well as a look ahead to several new compounds that are in the development pipeline.

Topics: Carbapenems; Cephalosporins; History, 20th Century; History, 21st Century; Humans; Monobactams; Penicillins; beta-Lactam Resistance; beta-Lactamase Inhibitors

PubMed: 27329032
DOI: 10.1101/cshperspect.a025247

Authors: Anne Santerre Henriksen, Katy Jeannot, Antonio Oliver...

UNLABELLED

Carbapenem-resistant and spp. represent major threats and have few approved therapeutic options. Non-‍fermenting Gram-negative isolates were collected from hospitalized inpatients from 49 sites in 6 European countries between 01 January 2020 and 31 December 2020 and underwent susceptibility testing against cefiderocol and β-lactam/β-lactamase inhibitor combinations. Meropenem-resistant (MIC >8 mg/L), cefiderocol-susceptible isolates were analyzed by PCR, and cefiderocol-resistant isolates were analyzed by whole-genome sequencing to identify resistance mechanisms. Overall, 1,451 (950 . ; 501 spp.) isolates were collected, commonly from the respiratory tract (42.0% and 39.3%, respectively). Cefiderocol susceptibility was higher than ‍β‍-‍l‍a‍c‍t‍a‍m‍/‍β‍-‍l‍a‍c‍t‍a‍mase‍ inhibitor combinations against (98.9% vs 83.3%-91.4%), and resistant to meropenem ( = 139; 97.8% vs 12.2%-59.7%), β-lactam/β-lactamase inhibitor combinations (93.6%-98.1% vs 10.7%-71.8%), and both meropenem and ceftazidime-avibactam (96.7% vs 5.0%-‍‍45.0%) or ‍ceftolozane-tazobactam (98.4% vs 8.1%-54.8%), respectively. Cefiderocol and sulbactam-durlobactam susceptibilities were high against spp. (92.4% and 97.0%) and meropenem-resistant ‍spp. ( = 227; 85.0% and 93.8%) but lower against sulbactam-durlobactam- ( ‍= 15; 13.3%) and cefiderocol- ( = 38; 65.8%) resistant isolates, respectively. Among meropenem-resistant and spp., the most common β-‍‍lactamase genes were metallo-β-lactamases [30/139; (15/139)] and oxacillinases [215/227; (194/227)], respectively. Acquired β-lactamase genes were identified in 1/10 and 32/38 of cefiderocol-resistant and spp., and -like or mutations in 10/10 and 37/38, respectively. cefiderocol susceptibility was high against and spp., including meropenem-resistant isolates and those resistant to recent β-lactam/β-lactamase inhibitor combinations common in first-line treatment of European non-fermenters.

IMPORTANCE

This was the first study in which the activity of cefiderocol and non-licensed β-lactam/β-lactamase inhibitor combinations were directly compared against and spp., including meropenem- and β-lactam/β-lactamase inhibitor combination-resistant isolates. A notably large number of European isolates were collected. Meropenem resistance was defined according to the MIC breakpoint for high-dose meropenem, ensuring that data reflect antibiotic activity against isolates that would remain meropenem resistant in the clinic. Cefiderocol susceptibility was high against non-fermenters, and there was no apparent cross resistance between cefiderocol and β-lactam/β-lactamase inhibitor combinations, with the exception of sulbactam-durlobactam. These results provide insights into therapeutic options for infections due to resistant and spp. and indicate how early susceptibility testing of cefiderocol in parallel with β-lactam/β-lactamase inhibitor combinations will allow clinicians to choose the effective treatment(s) from all available options. This is particularly important as current treatment options against non-fermenters are limited.

Topics: Humans; Meropenem; Cefiderocol; beta-Lactamase Inhibitors; Pseudomonas aeruginosa; Lactams; Anti-Bacterial Agents; Cephalosporins; Pseudomonas Infections; Gram-Negative Bacteria; Acinetobacter; Microbial Sensitivity Tests; beta-Lactamases

PubMed: 38483164
DOI: 10.1128/spectrum.03836-23

Review

Authors: Jed F Fisher, Shahriar Mobashery

The title of this essay is as much a question as it is a statement. The discovery of the β-lactam antibiotics-including penicillins, cephalosporins, and carbapenems-as largely (if not exclusively) secondary metabolites of terrestrial fungi and bacteria, transformed modern medicine. The antibiotic β-lactams inactivate essential enzymes of bacterial cell-wall biosynthesis. Moreover, the ability of the β-lactams to function as enzyme inhibitors is of such great medical value, that inhibitors of the enzymes which degrade hydrolytically the β-lactams, the β-lactamases, have equal value. Given this privileged status for the β-lactam ring, it is therefore a disappointment that the exemplification of this ring in marine secondary metabolites is sparse. It may be that biologically active marine β-lactams are there, and simply have yet to be encountered. In this report, we posit a second explanation: that the value of the β-lactam to secure an ecological advantage in the marine environment might be compromised by its close structural similarity to the β-lactones of quorum sensing. The steric and reactivity similarities between the β-lactams and the β-lactones represent an outside-of-the-box opportunity for correlating new structures and new enzyme targets for the discovery of compelling biological activities.

Topics: beta-Lactams; Anti-Bacterial Agents; Penicillins; beta-Lactamases; Bacteria; Lactones; Oceans and Seas

PubMed: 36827127
DOI: 10.3390/md21020086

Review

Authors: Juan F Martin, Ruben Alvarez-Alvarez, Paloma Liras...

The human society faces a serious problem due to the widespread resistance to antibiotics in clinical practice. Most antibiotic biosynthesis gene clusters in actinobacteria contain genes for intrinsic self-resistance to the produced antibiotics, and it has been proposed that the antibiotic resistance genes in pathogenic bacteria originated in antibiotic-producing microorganisms. The model actinobacteria produces the β-lactam antibiotic cephamycin C, a class A β-lactamase, and the β lactamases inhibitor clavulanic acid, all of which are encoded in a gene supercluster; in addition, it synthesizes the β-lactamase inhibitory protein BLIP. The secreted clavulanic acid has a synergistic effect with the cephamycin produced by the same strain in the fight against competing microorganisms in its natural habitat. High levels of resistance to cephamycin/cephalosporin in actinobacteria are due to the presence (in their β-lactam clusters) of genes encoding PBPs which bind penicillins but not cephalosporins. We have revised the previously reported cephamycin C and clavulanic acid gene clusters and, in addition, we have searched for novel β-lactam gene clusters in protein databases. Notably, in and , the β-lactamases are retained in the cell wall and do not affect the intracellular formation of isopenicillin N/penicillin N. The activity of the β-lactamase in may be modulated by the β-lactamase inhibitory protein BLIP at the cell-wall level. Analysis of the β-lactam cluster in actinobacteria suggests that these clusters have been moved by horizontal gene transfer between different actinobacteria and have culminated in with the organization of an elaborated set of genes designed for fine tuning of antibiotic resistance and cell wall remodeling for the survival of this species. This article is focused specifically on the enigmatic connection between β-lactam biosynthesis and β-lactam resistance mechanisms in the producer actinobacteria.

Topics: Actinobacteria; Anti-Bacterial Agents; Cephalosporins; Cephamycins; Clavulanic Acid; Penicillin-Binding Proteins; Penicillins; beta-Lactamase Inhibitors; beta-Lactamases; beta-Lactams

PubMed: 35628478
DOI: 10.3390/ijms23105662

Activity of cefiderocol and innovative β-lactam/β-lactamase inhibitor combinations against isogenic strains of Escherichia coli expressing single and double β-lactamases under high and low permeability conditions.

Authors: Tania Blanco-Martín, Isaac Alonso-García, Lucía González-Pinto...

OBJECTIVES

To analyse the impact of the most clinically relevant β-lactamases and their interplay with low outer membrane permeability on the activity of cefiderocol, ceftazidime/avibactam, aztreonam/avibactam, cefepime/enmetazobactam, cefepime/taniborbactam, cefepime/zidebactam, imipenem/relebactam, meropenem/vaborbactam, meropenem/xeruborbactam and meropenem/nacubactam against recombinant Escherichia coli strains.

METHODS

We constructed 82 E. coli laboratory transformants expressing the main β-lactamases circulating in Enterobacterales (70 expressing single β-lactamase and 12 producing double carbapenemase) under high (E. coli TG1) and low (E. coli HB4) permeability conditions. Antimicrobial susceptibility testing was determined by reference broth microdilution.

RESULTS

Aztreonam/avibactam, cefepime/zidebactam, cefiderocol, meropenem/xeruborbactam and meropenem/nacubactam were active against all E. coli TG1 transformants. Imipenem/relebactam, meropenem/vaborbactam, cefepime/taniborbactam and cefepime/enmetazobactam were also highly active, but unstable against most of MBL-producing transformants. Combination of β-lactamases with porin deficiency (E. coli HB4) did not significantly affect the activity of aztreonam/avibactam, cefepime/zidebactam, cefiderocol or meropenem/nacubactam, but limited the effectiveness of the rest of carbapenem- and cefepime-based combinations. Double-carbapenemase production resulted in the loss of activity of most of the compounds tested, an effect particularly evident for those E. coli HB4 transformants in which MBLs were present.

CONCLUSIONS

Our findings highlight the promising activity that cefiderocol and new β-lactam/β-lactamase inhibitors have against recombinant E. coli strains expressing widespread β-lactamases, including when these are combined with low permeability or other enzymes. Aztreonam/avibactam, cefiderocol, cefepime/zidebactam and meropenem/nacubactam will help to mitigate to some extent the urgency of new compounds able to resist MBL action, although NDM enzymes represent a growing challenge against which drug development efforts are still needed.

Topics: Escherichia coli; beta-Lactamases; Cephalosporins; Microbial Sensitivity Tests; beta-Lactamase Inhibitors; Azabicyclo Compounds; Anti-Bacterial Agents; Drug Combinations; Cyclooctanes; Cefiderocol; Ceftazidime; Cefepime; Boronic Acids; Meropenem; Aztreonam; Imipenem; Bacterial Proteins; Heterocyclic Compounds, 1-Ring; Cell Membrane Permeability; Borinic Acids; Carboxylic Acids; Lactams; Triazoles

PubMed: 38513748
DOI: 10.1016/j.ijantimicag.2024.107150

Review

Authors: Guangrong Meng, Jin Zhang, Michal Szostak...

In this contribution, we provide a comprehensive overview of acyclic twisted amides, covering the literature since 1993 (the year of the first recognized report on acyclic twisted amides) through June 2020. The review focuses on classes of acyclic twisted amides and their key structural properties, such as amide bond twist and nitrogen pyramidalization, which are primarily responsible for disrupting to π* conjugation. Through discussing acyclic twisted amides in comparison with the classic bridged lactams and conformationally restricted cyclic fused amides, the reader is provided with an overview of amidic distortion that results in novel conformational features of acyclic amides that can be exploited in various fields of chemistry ranging from organic synthesis and polymers to biochemistry and structural chemistry and the current position of acyclic twisted amides in modern chemistry.

Topics: Amides; Chemistry Techniques, Synthetic; Lactams; Molecular Conformation; Nitrogen

PubMed: 34406005
DOI: 10.1021/acs.chemrev.1c00225

potency of xeruborbactam in combination with multiple β-lactam antibiotics in comparison with other β-lactam/β-lactamase inhibitor (BLI) combinations against carbapenem-resistant and extended-spectrum β-lactamase-producing .

Authors: Olga Lomovskaya, Mariana Castanheira, Jill Lindley...

Recently, several β-lactam (BL)/β-lactamase inhibitor (BLI) combinations have entered clinical testing or have been marketed for use, but limited direct comparative studies of their activity exist. Xeruborbactam (XER, also known as QPX7728), which is undergoing clinical development, is a cyclic boronate BLI with potent inhibitory activity against serine (serine β-lactamase) and metallo-β-lactamases (MBLs). The objectives of this study were (i) to compare the potency and spectrum of β-lactamase inhibition by various BLIs in biochemical assays using purified β-lactamases and in microbiological assays using the panel of laboratory strains expressing diverse serine and metallo-β-lactamases and (ii) to compare the potency of XER in combination with multiple β-lactam antibiotics to that of other BL/BLI combinations in head-to-head testing against recent isolates of carbapenem-resistant (CRE). Minimal inhibitory concentrations (MICs) of XER combinations were tested with XER at fixed 4 or 8 µg/mL, and MIC testing was conducted in a blinded fashion using Clinical and Laboratory Standards Institute reference methods. Xeruborbactam and taniborbactam (TAN) were the only BLIs that inhibited clinically important MBLs. The spectrum of activity of xeruborbactam included several MBLs identified in e.g., and various IMP enzymes and NDM-9 that were not inhibited by taniborbactam. Xeruborbactam potency against the majority of purified β-lactamases was the highest in comparison with other BLIs. Meropenem-xeruborbactam (MEM-XER, fixed 8 µg/mL) was the most potent combination against MBL-negative CRE with MIC values of 0.125 µg/mL. MEM-XER and cefepime-taniborbactam (FEP-TAN) were the only BL/BLIs with activity against MBL-producing CREs; with MEM-XER (MIC of 1 µg/mL) being at least 16-fold more potent than FEP-TAN (MIC of 16 µg/mL). MEM-XER MIC values were ≤8 µg/mL for >90% of CRE, including both MBL-negative and MBL-positive isolates, with FEP-TAN MIC of >8 µg/mL. Xeruborbactam also significantly enhanced potency of other β-lactam antibiotics, including cefepime, ceftolozane, ceftriaxone, aztreonam, piperacillin, and ertapenem, against clinical isolates of that carried various class A, class C, and class D extended-spectrum β-lactamases and carbapenem-resistant , including metallo-β-lactamase-producing isolates. These results strongly support further clinical development of xeruborbactam combinations.

Topics: beta-Lactamase Inhibitors; Anti-Bacterial Agents; Carbapenems; beta Lactam Antibiotics; Cefepime; Lactams; beta-Lactamases; Serine; Microbial Sensitivity Tests; Azabicyclo Compounds

PubMed: 37800963
DOI: 10.1128/aac.00440-23

Review

Authors: Frank Hollmann, Selin Kara, Diederik J Opperman...

Cyclic esters and amides (lactones and lactams) are important active ingredients and polymer building blocks. In recent years, numerous biocatalytic methods for their preparation have been developed including enzymatic and chemoenzymatic Baeyer-Villiger oxidations, oxidative lactonisation of diols, and reductive lactonisation and lactamisation of ketoesters. The current state of the art of these methods is reviewed.

Topics: Biocatalysis; Chemistry Techniques, Synthetic; Hydrolases; Lactams; Lactones; Mixed Function Oxygenases; Oxidation-Reduction

PubMed: 30256534
DOI: 10.1002/asia.201801180

Review

Authors: Ariane F Bertonha, Caio C L Silva, Karina T Shirakawa...

Bacterial cell wall formation is essential for cellular survival and morphogenesis. The peptidoglycan (PG), a heteropolymer that surrounds the bacterial membrane, is a key component of the cell wall, and its multistep biosynthetic process is an attractive antibacterial development target. Penicillin-binding proteins (PBPs) are responsible for cross-linking PG stem peptides, and their central role in bacterial cell wall synthesis has made them the target of successful antibiotics, including β-lactams, that have been used worldwide for decades. Following the discovery of penicillin, several other compounds with antibiotic activity have been discovered and, since then, have saved millions of lives. However, since pathogens inevitably become resistant to antibiotics, the search for new active compounds is continuous. The present review highlights the ongoing development of inhibitors acting mainly in the transpeptidase domain of PBPs with potential therapeutic applications for the development of new antibiotic agents. Both the critical aspects of the strategy, design, and structure-activity relationships (SAR) are discussed, covering the main published articles over the last 10 years. Some of the molecules described display activities against main bacterial pathogens and could open avenues toward the development of new, efficient antibacterial drugs.

Topics: Penicillin-Binding Proteins; Anti-Bacterial Agents; beta-Lactams; Penicillins; Bacteria; Bacterial Proteins

PubMed: 38030964
DOI: 10.1177/15353702231208407

Review

Authors: Tom Armstrong, Samuel Jacob Fenn, Kim R Hardie...

Carbapenems are potent members of the β-lactam family that inhibit bacterial cell-wall biosynthesis inhibitors . They are highly effective against Gram-negative and Gram-positive drug-resistant infections . As such, carbapenems are typically reserved as an antibiotic of last resort. The WHO lists meropenem as an essential medicine. Nausea and vomiting are reported in ≤20% of carbapenem recipients, with 1.5% suffering seizures. Enzymatic hydrolysis of the βlactam ring is the main driver of clinical resistance. These enzymes can be classified as Class A, B and D. Classes A and D are serine βlactamases, whereas Class B rely on metal-mediated hydrolysis, typically through zinc.

Topics: Anti-Bacterial Agents; Carbapenems; Meropenem; beta-Lactamases; beta-Lactams

PubMed: 34889726
DOI: 10.1099/jmm.0.001462