Targeting β-Lactamases to Fight Antimicrobial Resistance

A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Mechanism and Evolution of Antibiotic Resistance".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 8031

Special Issue Editor

Life Sciences & Chemistry, Jacobs University Bremen gGmbH, 28759 Bremen, Germany
Interests: β-lactams; enzymology of β-lactamases; β-lactamase inhibitiors; antibiotic resistance; antibiotic discovery

Special Issue Information

Dear colleagues,

β-Lactamases constitute the primary means of resistance that bacteria have towards the widely used β-lactam antibiotics. These enzymes hydrolyze not only the amide bond of the four-membered β-lactam ring that gives its name to this class of antibiotics, but also the larger β-lactam ring found in some natural products and derivatives. Only a handful of β-lactamases were known in the early 1970s, but the number of β-lactamases has increased dramatically in the face of intense selection pressure imposed by the human use of β-lactam antibiotics. 

There are more than seven thousand β-lactamase variants recorded, belonging to four principal molecular classes, each with a different hydrolytic mechanism. Three classes, A, C, and D, have a serine residue in the catalytic center that acts as the primary nucleophile to attack the amide bond to form an acyl-enzyme intermediate. A water molecule is activated by a different mechanism in each of the three classes to hydrolyze the ester bond in the acyl intermediate, regenerating the free enzymes. The class B enzymes use zinc ions bound in the catalytic center to activate a water molecule for direct attack on the amide bond. Although substrate specificities vary considerably within each class, none of the marketed β-lactam antibiotics can resist destruction by all enzymes. 

Starting with clavulanic acid, a natural inhibitor of the serine enzymes discovered in the 1970s and introduced into clinical practice in 1981 combined with amoxicillin, combinations of a β-lactamase-labile antibiotic with a specific β-lactamase inhibitor have now become an important way to combat the growing threat from β-lactamase-mediated resistance. In this Special Issue, we will explore different approaches to developing inhibitors that will overcome the broad array of β-lactamases now distributed in pathogenic bacteria.

Prof. Dr. Malcolm Page
Guest Editor

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Keywords

  • β-lactam resistance
  • β-lactamase inhibitor
  • class A β-lactamase
  • class B β-lactamase
  • class C β-lactamase
  • class D β-lactamase

Published Papers (3 papers)

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Research

11 pages, 672 KiB  
Article
Comparative Effectiveness of Ampicillin/Sulbactam versus Cefazolin as Targeted Therapy for Bacteremia Caused by Beta-Lactamase-Producing Methicillin-Sensitive Staphylococcus aureus: A Single-Center Retrospective Study
by Jun Hirai, Nobuhiro Asai, Mao Hagihara, Takaaki Kishino, Hideo Kato, Daisuke Sakanashi, Wataru Ohashi and Hiroshige Mikamo
Antibiotics 2022, 11(11), 1505; https://doi.org/10.3390/antibiotics11111505 - 28 Oct 2022
Cited by 2 | Viewed by 2237
Abstract
Cefazolin (CFZ) is the first-line treatment for beta-lactamase-producing methicillin-sensitive Staphylococcus aureus (BP-MSSA) infection. In 2019, Japan experienced a CFZ shortage because of foreign object inclusion in a batch. Ampicillin/sulbactam (SAM) was preferred in many cases as definitive therapy for the treatment of BP-MSSA [...] Read more.
Cefazolin (CFZ) is the first-line treatment for beta-lactamase-producing methicillin-sensitive Staphylococcus aureus (BP-MSSA) infection. In 2019, Japan experienced a CFZ shortage because of foreign object inclusion in a batch. Ampicillin/sulbactam (SAM) was preferred in many cases as definitive therapy for the treatment of BP-MSSA bacteremia to preserve broad-spectrum antibiotic stock. However, there are no previous studies reporting the clinical efficacy of SAM for BP-MSSA bacteremia. We aimed to compare the clinical efficacy and adverse effects of SAM versus CFZ in patients with BP-MSSA bacteremia. In total, 41 and 30 patients treated with SAM and CFZ, respectively, were identified. The baseline characteristics were similar in both groups. No significant differences were observed in length of hospital stay and all 30-day mortality between the two groups (p = 0.270 and 0.643, respectively). Moreover, no intergroup difference in 90-day mortality was found (hazard ratio 1.02, 95% confidential interval 0.227–4.53). Adverse effects, such as liver dysfunction, were less in the CFZ group than in the SAM group (p = 0.030). Therefore, in cases of poor CFZ supply or in patients allergic to CFZ and penicillinase-stable penicillins, SAM can be an effective therapeutic option for bacteremia due to BP-MSSA with attention of adverse effects, such as liver dysfunction. Full article
(This article belongs to the Special Issue Targeting β-Lactamases to Fight Antimicrobial Resistance)
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10 pages, 2321 KiB  
Article
Studies on the Reactions of Biapenem with VIM Metallo β-Lactamases and the Serine β-Lactamase KPC-2
by Anka Lucic, Tika R. Malla, Karina Calvopiña, Catherine L. Tooke, Jürgen Brem, Michael A. McDonough, James Spencer and Christopher J. Schofield
Antibiotics 2022, 11(3), 396; https://doi.org/10.3390/antibiotics11030396 - 16 Mar 2022
Cited by 8 | Viewed by 2350
Abstract
Carbapenems are important antibacterials and are both substrates and inhibitors of some β-lactamases. We report studies on the reaction of the unusual carbapenem biapenem, with the subclass B1 metallo-β-lactamases VIM-1 and VIM-2 and the class A serine-β-lactamase KPC-2. X-ray diffraction studies with VIM-2 [...] Read more.
Carbapenems are important antibacterials and are both substrates and inhibitors of some β-lactamases. We report studies on the reaction of the unusual carbapenem biapenem, with the subclass B1 metallo-β-lactamases VIM-1 and VIM-2 and the class A serine-β-lactamase KPC-2. X-ray diffraction studies with VIM-2 crystals treated with biapenem reveal the opening of the β-lactam ring to form a mixture of the (2S)-imine and enamine complexed at the active site. NMR studies on the reactions of biapenem with VIM-1, VIM-2, and KPC-2 reveal the formation of hydrolysed enamine and (2R)- and (2S)-imine products. The combined results support the proposal that SBL/MBL-mediated carbapenem hydrolysis results in a mixture of tautomerizing enamine and (2R)- and (2S)-imine products, with the thermodynamically favoured (2S)-imine being the major observed species over a relatively long-time scale. The results suggest that prolonging the lifetimes of β-lactamase carbapenem complexes by optimising tautomerisation of the nascently formed enamine to the (2R)-imine and likely more stable (2S)-imine tautomer is of interest in developing improved carbapenems. Full article
(This article belongs to the Special Issue Targeting β-Lactamases to Fight Antimicrobial Resistance)
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15 pages, 1292 KiB  
Article
Association of blaVIM-2, blaPDC-35, blaOXA-10, blaOXA-488 and blaVEB-9 β-Lactamase Genes with Resistance to Ceftazidime–Avibactam and Ceftolozane–Tazobactam in Multidrug-Resistant Pseudomonas aeruginosa
by Mazen A. Sid Ahmed, Faisal Ahmad Khan, Hamad Abdel Hadi, Sini Skariah, Ali A. Sultan, Abdul Salam, Abdul Latif Al Khal, Bo Söderquist, Emad Bashir Ibrahim, Ali S. Omrani and Jana Jass
Antibiotics 2022, 11(2), 130; https://doi.org/10.3390/antibiotics11020130 - 19 Jan 2022
Cited by 7 | Viewed by 2761
Abstract
Ceftazidime–avibactam and ceftolozane–tazobactam are approved for the treatment of complicated Gram-negative bacterial infections including multidrug-resistant (MDR) Pseudomonas aeruginosa. Resistance to both agents has been reported, but the underlying mechanisms have not been fully explored. This study aimed to correlate β-lactamases with phenotypic [...] Read more.
Ceftazidime–avibactam and ceftolozane–tazobactam are approved for the treatment of complicated Gram-negative bacterial infections including multidrug-resistant (MDR) Pseudomonas aeruginosa. Resistance to both agents has been reported, but the underlying mechanisms have not been fully explored. This study aimed to correlate β-lactamases with phenotypic resistance to ceftazidime–avibactam and/or ceftolozane–tazobactam in MDR-P. aeruginosa from Qatar. A total of 525 MDR-P. aeruginosa isolates were collected from clinical specimens between 2014 and 2017. Identification and antimicrobial susceptibility were performed by the BD PhoenixTM system and gradient MIC test strips. Of the 75 sequenced MDR isolates, 35 (47%) were considered as having difficult-to-treat resistance, and 42 were resistant to ceftazidime–avibactam (37, 49.3%), and/or ceftolozane–tazobactam (40, 53.3%). They belonged to 12 sequence types, with ST235 being predominant (38%). Most isolates (97.6%) carried one or more β-lactamase genes, with blaOXA-488 (19%) and blaVEB-9 (45.2%) being predominant. A strong association was detected between class B β-lactamase genes and both ceftazidime–avibactam and ceftolozane–tazobactam resistance, while class A genes were associated with ceftolozane–tazobactam resistance. Co-resistance to ceftazidime–avibactam and ceftolozane–tazobactam correlated with the presence of blaVEB-9, blaPDC-35, blaVIM-2, blaOXA-10 and blaOXA-488. MDR-P. aeruginosa isolates resistant to both combination drugs were associated with class B β-lactamases (blaVIM-2) and class D β-lactamases (blaOXA-10), while ceftolozane–tazobactam resistance was associated with class A (blaVEB-9), class C (blaVPDC-35), and class D β-lactamases (blaOXA-488). Full article
(This article belongs to the Special Issue Targeting β-Lactamases to Fight Antimicrobial Resistance)
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