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Special Issue "New Beta-Lactams, Beta-Lactamase Inhibitors and Targets for Beta-Lactamase Production Blockade: Powerful Allies against Multidrug-Resistant Pathogens"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Microbiology".

Deadline for manuscript submissions: 31 May 2021.

Special Issue Editor

Dr. Carlos Juan Nicolau
E-Mail Website
Guest Editor
Hospital Universitari Son Espases- Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain
Interests: nosocomial gram-negative pathogens; antibiotic resistance; peptidoglycan biology; host-pathogen interaction; virulence; cell-wall-targeting immunity

Special Issue Information

Dear Colleagues,

Antibiotic resistance, especially referred to nosocomial opportunistic bacterial pathogens, is already an undeniable threat for public health worldwide, with obvious clinical and economic consequences. In the specific context of beta-lactam antibiotics, the threat is certainly not less severe, given their generalized use. Nevertheless, the appearance of new therapeutic options brings us a reason for hope. Among these therapeutic allies, we acknowledge: (i) the appearance of novel beta-lactam-related drugs (such as cefiderocol or ceftobiprole); (ii) the use of new antibiotic combinations including beta-lactamase activity inhibitors (for instance ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/relebactam, and meropenem-vaborbactam), and (iii) the research on unexplored targets leading to the blockade of intrinsic beta-lactamases production (usually related to cell wall metabolism, such as AmpG or NagZ proteins, which have been shown to be essential for the correct expression of intrinsic beta-lactamases and full virulence in Pseudomonas aeruginosa and related species). Reviews and research papers related to these topics (referring to either Gram-positive or Gram-negative pathogens) are welcome for this Special Issue.

Dr. Carlos Juan Nicolau
Guest Editor

Manuscript Submission Information

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Keywords

  • Antibiotic resistance
  • ESKAPE pathogens
  • MRSA
  • Enterobacteriaceae
  • Acinetobacter baumannii
  • Pseudomonas aeruginosa
  • horizontally acquired beta-lactamases
  • carbapenemases
  • beta-lactamase inhibitors
  • intrinsic beta-lactamases
  • peptidoglycan recycling
  • cell wall metabolism
  • virulence
  • AmpC cephalosporinase
  • cefiderocol
  • ceftobiprole
  • ceftazidime/avibactam
  • ceftolozane/tazobactam
  • imipenem/relebactam
  • meropenem/vaborbactam

Published Papers (7 papers)

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Research

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Open AccessArticle
Molecular Basis of AmpC β-Lactamase Induction by Avibactam in Pseudomonas aeruginosa: PBP Occupancy, Live Cell Binding Dynamics and Impact on Resistant Clinical Isolates Harboring PDC-X Variants
Int. J. Mol. Sci. 2021, 22(6), 3051; https://doi.org/10.3390/ijms22063051 - 17 Mar 2021
Viewed by 355
Abstract
Avibactam belongs to the new class of diazabicyclooctane β-lactamase inhibitors. Its inhibitory spectrum includes class A, C and D enzymes, including P. aeruginosa AmpC. Nonetheless, recent reports have revealed strain-dependent avibactam AmpC induction. In the present work, we wanted to assess the mechanistic [...] Read more.
Avibactam belongs to the new class of diazabicyclooctane β-lactamase inhibitors. Its inhibitory spectrum includes class A, C and D enzymes, including P. aeruginosa AmpC. Nonetheless, recent reports have revealed strain-dependent avibactam AmpC induction. In the present work, we wanted to assess the mechanistic basis underlying AmpC induction and determine if derepressed PDC-X mutated enzymes from ceftazidime/avibactam-resistant clinical isolates were further inducible. We determined avibactam concentrations that half-maximally inhibited (IC50) bocillin FL binding. Inducer β-lactams were also studied as comparators. Live cells’ time-course penicillin-binding proteins (PBPs) occupancy of avibactam was studied. To assess the ampC induction capacity of avibactam and comparators, qRT-PCR was performed in wild-type PAO1, PBP4, triple PBP4, 5/6 and 7 knockout derivatives and two ceftazidime/avibactam-susceptible/resistant XDR clinical isolates belonging to the epidemic high-risk clone ST175. PBP4 inhibition was observed for avibactam and β-lactam comparators. Induction capacity was consistently correlated with PBP4 binding affinity. Outer membrane permeability-limited PBP4 binding was observed in the live cells’ assay. As expected, imipenem and cefoxitin showed strong induction in PAO1, especially for carbapenem; avibactam induction was conversely weaker. Overall, the inducer effect was less remarkable in ampC-derepressed mutants and nonetheless absent upon avibactam exposure in the clinical isolates harboring mutated AmpC variants and their parental strains. Full article
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Open AccessArticle
The Role of Rigid Residues in Modulating TEM-1 β-Lactamase Function and Thermostability
Int. J. Mol. Sci. 2021, 22(6), 2895; https://doi.org/10.3390/ijms22062895 - 12 Mar 2021
Viewed by 365
Abstract
The relationship between protein motions (i.e., dynamics) and enzymatic function has begun to be explored in β-lactamases as a way to advance our understanding of these proteins. In a recent study, we analyzed the dynamic profiles of TEM-1 (a ubiquitous class A β-lactamase) [...] Read more.
The relationship between protein motions (i.e., dynamics) and enzymatic function has begun to be explored in β-lactamases as a way to advance our understanding of these proteins. In a recent study, we analyzed the dynamic profiles of TEM-1 (a ubiquitous class A β-lactamase) and several ancestrally reconstructed homologues. A chief finding of this work was that rigid residues that were allosterically coupled to the active site appeared to have profound effects on enzyme function, even when separated from the active site by many angstroms. In the present work, our aim was to further explore the implications of protein dynamics on β-lactamase function by altering the dynamic profile of TEM-1 using computational protein design methods. The Rosetta software suite was used to mutate amino acids surrounding either rigid residues that are highly coupled to the active site or to flexible residues with no apparent communication with the active site. Experimental characterization of ten designed proteins indicated that alteration of residues surrounding rigid, highly coupled residues, substantially affected both enzymatic activity and stability; in contrast, native-like activities and stabilities were maintained when flexible, uncoupled residues, were targeted. Our results provide additional insight into the structure-function relationship present in the TEM family of β-lactamases. Furthermore, the integration of computational protein design methods with analyses of protein dynamics represents a general approach that could be used to extend our understanding of the relationship between dynamics and function in other enzyme classes. Full article
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Open AccessArticle
Structural Study of Metal Binding and Coordination in Ancient Metallo-β-Lactamase PNGM-1 Variants
Int. J. Mol. Sci. 2020, 21(14), 4926; https://doi.org/10.3390/ijms21144926 - 12 Jul 2020
Viewed by 1238
Abstract
The increasing incidence of community- and hospital-acquired infections with multidrug-resistant (MDR) bacteria poses a critical threat to public health and the healthcare system. Although β-lactam antibiotics are effective against most bacterial infections, some bacteria are resistant to β-lactam antibiotics by producing β-lactamases. Among [...] Read more.
The increasing incidence of community- and hospital-acquired infections with multidrug-resistant (MDR) bacteria poses a critical threat to public health and the healthcare system. Although β-lactam antibiotics are effective against most bacterial infections, some bacteria are resistant to β-lactam antibiotics by producing β-lactamases. Among β-lactamases, metallo-β-lactamases (MBLs) are especially worrisome as only a few inhibitors have been developed against them. In MBLs, the metal ions play an important role as they coordinate a catalytic water molecule that hydrolyzes β-lactam rings. We determined the crystal structures of different variants of PNGM-1, an ancient MBL with additional tRNase Z activity. The variants were generated by site-directed mutagenesis targeting metal-coordinating residues. In PNGM-1, both zinc ions are coordinated by six coordination partners in an octahedral geometry, and the zinc-centered octahedrons share a common face. Structures of the PNGM-1 variants confirm that the substitution of a metal-coordinating residue causes the loss of metal binding and β-lactamase activity. Compared with PNGM-1, subclass B3 MBLs lack one metal-coordinating residue, leading to a shift in the metal-coordination geometry from an octahedral to tetrahedral geometry. Our results imply that a subtle change in the metal-binding site of MBLs can markedly change their metal-coordination geometry and catalytic activity. Full article
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Review

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Open AccessReview
The Odd Couple(s): An Overview of Beta-Lactam Antibiotics Bearing More Than One Pharmacophoric Group
Int. J. Mol. Sci. 2021, 22(2), 617; https://doi.org/10.3390/ijms22020617 - 09 Jan 2021
Viewed by 753
Abstract
β-lactam antibiotics are among the most important and widely used antimicrobials worldwide and are comprised of a large family of compounds, obtained by chemical modifications of the common scaffolds. Usually these modifications include the addition of active groups, but less frequently, molecules were [...] Read more.
β-lactam antibiotics are among the most important and widely used antimicrobials worldwide and are comprised of a large family of compounds, obtained by chemical modifications of the common scaffolds. Usually these modifications include the addition of active groups, but less frequently, molecules were synthesized in which either two β-lactam rings were joined to create a single bifunctional compound, or the azetidinone ring was joined to another antibiotic scaffold or another molecule with a different activity, in order to create a molecule bearing two different pharmacophoric functions. In this review, we report some examples of these derivatives, highlighting their biological properties and discussing how this strategy can lead to the development of innovative antibiotics that can represent either novel weapons against the rampant increase of antimicrobial resistance, or molecules with a broader spectrum of action. Full article
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Open AccessReview
New Carbapenemase Inhibitors: Clearing the Way for the β-Lactams
Int. J. Mol. Sci. 2020, 21(23), 9308; https://doi.org/10.3390/ijms21239308 - 06 Dec 2020
Cited by 2 | Viewed by 840
Abstract
Carbapenem resistance is a major global health problem that seriously compromises the treatment of infections caused by nosocomial pathogens. Resistance to carbapenems mainly occurs via the production of carbapenemases, such as VIM, IMP, NDM, KPC and OXA, among others. Preclinical and clinical trials [...] Read more.
Carbapenem resistance is a major global health problem that seriously compromises the treatment of infections caused by nosocomial pathogens. Resistance to carbapenems mainly occurs via the production of carbapenemases, such as VIM, IMP, NDM, KPC and OXA, among others. Preclinical and clinical trials are currently underway to test a new generation of promising inhibitors, together with the recently approved avibactam, relebactam and vaborbactam. This review summarizes the main, most promising carbapenemase inhibitors synthesized to date, as well as their spectrum of activity and current stage of development. We particularly focus on β-lactam/β-lactamase inhibitor combinations that could potentially be used to treat infections caused by carbapenemase-producer pathogens of critical priority. The emergence of these new combinations represents a step forward in the fight against antimicrobial resistance, especially in regard to metallo-β-lactamases and carbapenem-hydrolysing class D β-lactamases, not currently inhibited by any clinically approved inhibitor. Full article
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Open AccessReview
Emerging Strategies to Combat β-Lactamase Producing ESKAPE Pathogens
Int. J. Mol. Sci. 2020, 21(22), 8527; https://doi.org/10.3390/ijms21228527 - 12 Nov 2020
Cited by 2 | Viewed by 1176
Abstract
Since the discovery of penicillin by Alexander Fleming in 1929 as a therapeutic agent against staphylococci, β-lactam antibiotics (BLAs) remained the most successful antibiotic classes against the majority of bacterial strains, reaching a percentage of 65% of all medical prescriptions. Unfortunately, the emergence [...] Read more.
Since the discovery of penicillin by Alexander Fleming in 1929 as a therapeutic agent against staphylococci, β-lactam antibiotics (BLAs) remained the most successful antibiotic classes against the majority of bacterial strains, reaching a percentage of 65% of all medical prescriptions. Unfortunately, the emergence and diversification of β-lactamases pose indefinite health issues, limiting the clinical effectiveness of all current BLAs. One solution is to develop β-lactamase inhibitors (BLIs) capable of restoring the activity of β-lactam drugs. In this review, we will briefly present the older and new BLAs classes, their mechanisms of action, and an update of the BLIs capable of restoring the activity of β-lactam drugs against ESKAPE (Enterococcus spp., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) pathogens. Subsequently, we will discuss several promising alternative approaches such as bacteriophages, antimicrobial peptides, nanoparticles, CRISPR (clustered regularly interspaced short palindromic repeats) cas technology, or vaccination developed to limit antimicrobial resistance in this endless fight against Gram-negative pathogens. Full article
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Open AccessReview
Promiscuous Enzyme Activity as a Driver of Allo and Iso Convergent Evolution, Lessons from the β-Lactamases
Int. J. Mol. Sci. 2020, 21(17), 6260; https://doi.org/10.3390/ijms21176260 - 29 Aug 2020
Cited by 1 | Viewed by 848
Abstract
The probability of the evolution of a character depends on two factors: the probability of moving from one character state to another character state and the probability of the new character state fixation. The more the evolution of a character is probable, the [...] Read more.
The probability of the evolution of a character depends on two factors: the probability of moving from one character state to another character state and the probability of the new character state fixation. The more the evolution of a character is probable, the more the convergent evolution will be witnessed, and consequently, convergent evolution could mean that the convergent character evolution results as a combination of these two factors. We investigated this phenomenon by studying the convergent evolution of biochemical functions. For the investigation we used the case of β-lactamases. β-lactamases hydrolyze β-lactams, which are antimicrobials able to block the DD-peptidases involved in bacterial cell wall synthesis. β-lactamase activity is present in two different superfamilies: the metallo-β-lactamase and the serine β-lactamase. The mechanism used to hydrolyze the β-lactam is different for the two superfamilies. We named this kind of evolution an allo-convergent evolution. We further showed that the β-lactamase activity evolved several times within each superfamily, a convergent evolution type that we named iso-convergent evolution. Both types of convergent evolution can be explained by the two evolutionary mechanisms discussed above. The probability of moving from one state to another is explained by the promiscuous β-lactamase activity present in the ancestral sequences of each superfamily, while the probability of fixation is explained in part by positive selection, as the organisms having β-lactamase activity allows them to resist organisms that secrete β-lactams. Indeed, an organism that has a mutation that increases the β-lactamase activity will be selected, as the organisms having this activity will have an advantage over the others. Full article
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