Structural Insights into the TLA-3 Extended-Spectrum β-Lactamase and Its Inhibition by Avibactam and OP0595

Jin, Wei; Wachino, Jun-ichi; Yamaguchi, Yoshihiro; Kimura, Kouji; Kumar, Ashish; Yamada, Masao; Morinaka, Akihiro; Sakamaki, Yoshiaki; Yonezawa, Minoru; Kurosaki, Hiromasa; Arakawa, Yoshichika

doi:10.1128/aac.00501-17

Cited by 12 publications

(13 citation statements)

References 35 publications

(35 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, recognizing that PER-2 is more hydrophobic than TLA-3, a displacement of the deacylating water in PER-2:AVI seems unlikely because the inhibition parameters k 2 /K and k off for both PER-2 and TLA-3 are very similar (2,200 M Ϫ1 s Ϫ1 and 0.0004 s Ϫ1 versus 3,250 M Ϫ1 s Ϫ1 and 0.00096 s Ϫ1 , respectively). In turn, the apparent K i (K i app ) for TLA-3 (1.71 M) is 12-fold lower than that for PER-2 (16), which is also greatly increased in Arg220 variants.…”

Section: Resultsmentioning

confidence: 89%

Structural Insights into the Inhibition of the Extended-Spectrum β-Lactamase PER-2 by Avibactam

Ruggiero

Papp-Wallace

Brunetti

et al. 2019

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The diazabicyclooctane (DBO) avibactam (AVI) reversibly inactivates most serine-β-lactamases. Previous investigations showed that inhibition constants of AVI toward class A PER-2 are reminiscent of values observed for class C and D β-lactamases (i.e., k2/K of ≈103 M−1 s−1) but lower than other class A β-lactamases (i.e., k2/K = 104 to 105 M−1 s−1). Herein, biochemical and structural studies were conducted with PER-2 and AVI to explore these differences. Furthermore, biochemical studies on Arg220 and Thr237 variants with AVI were conducted to gain deeper insight into the mechanism of PER-2 inactivation. The main biochemical and structural observations revealed the following: (i) both amino-acid substitutions in Arg220 and the rich hydrophobic content in the active site hinder the binding of catalytic waters and acylation, impairing AVI inhibition; (ii) movement of Ser130 upon binding of AVI favors the formation of a hydrogen bond with the sulfate group of AVI; and (iii) the Thr237Ala substitution alters the AVI inhibition constants. The acylation constant (k2/K) of PER-2 by AVI is primarily influenced by stabilizing hydrogen bonds involving AVI and important residues such as Thr237 and Arg220. (Variants in Arg220 demonstrate a dramatic reduction in k2/K.) We also observed that displacement of Ser130 side chain impairs AVI acylation, an observation not made in other extended-spectrum β-lactamases (ESBLs). Comparatively, relebactam combined with a β-lactam is more potent against Escherichia coli producing PER-2 variants than β-lactam–AVI combinations. Our findings provide a rationale for evaluating the utility of the currently available DBO inhibitors against unique ESBLs like PER-2 and anticipate the effectiveness of these inhibitors toward variants that may eventually be selected upon AVI usage.

show abstract

Section: Resultsmentioning

confidence: 89%

Structural Insights into the Inhibition of the Extended-Spectrum β-Lactamase PER-2 by Avibactam

Ruggiero

Papp-Wallace

Brunetti

et al. 2019

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…4A). Presently, the crystal structures of six class A ␤-lactamases (TLA-3 [38], L2 [39], SHV-1 [40], KPC-2 [40], CTX-M-15 [41,42], BlaC [43]) in complex with avibactam have been reported, and while they share many similarities, interesting differences are also present. For VCC-1, a well-defined electron density can be observed for avibactam covalently bound to the side chain oxygen of Ser70 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Molecular Basis for the Potent Inhibition of the Emerging Carbapenemase VCC-1 by Avibactam

Mangat

Vadlamani

Holicek

et al. 2019

Antimicrob Agents Chemother

View full text Add to dashboard Cite

In 2016, we identified a new class A carbapenemase, VCC-1, in a nontoxigenic Vibrio cholerae strain that had been isolated from retail shrimp imported into Canada for human consumption. Shortly thereafter, seven additional VCC-1producing V. cholerae isolates were recovered along the German coastline. These isolates appear to have acquired the VCC-1 gene (bla VCC-1 ) independently from the Canadian isolate, suggesting that bla VCC-1 is mobile and widely distributed. VCC-1 hydrolyzes penicillins, cephalothin, aztreonam, and carbapenems and, like the broadly disseminated class A carbapenemase KPC-2, is only weakly inhibited by clavulanic acid or tazobactam. Although VCC-1 has yet to be observed in the clinic, its encroachment into aquaculture and other areas with human activity suggests that the enzyme may be emerging as a public health threat. To preemptively address this threat, we examined the structural and functional biology of VCC-1 against the FDAapproved non-␤-lactam-based inhibitor avibactam. We found that avibactam restored the in vitro sensitivity of V. cholerae to meropenem, imipenem, and ertapenem. The acylation efficiency was lower for VCC-1 than for KPC-2 and akin to that of Pseudomonas aeruginosa PAO1 AmpC (k 2 /K i ϭ 3.0 ϫ 10 3 M Ϫ1 s Ϫ1 ). The tertiary structure of VCC-1 is similar to that of KPC-2, and they bind avibactam similarly; however, our analyses suggest that VCC-1 may be unable to degrade avibactam, as has been found for KPC-2. Based on our prior genomics-based surveillance, we were able to target VCC-1 for detailed molecular studies to gain early insights that could be used to combat this carbapenemase in the future.

show abstract

“…As for the plasmid-mediated novel TLA-3-type ESBL, 42 the mode of inhibition with a new β-lactamase inhibitor, OP0595, was investigated by an X-ray crystallographic analysis. 43 Phylogenetic relation among the principal β-lactamases is shown in Figure S1, together with those characterized by us ( Table 2).…”

Section: My Collaborators Identified Various Novel β-Lactamasesmentioning

confidence: 87%

Systematic research to overcome newly emerged multidrug‐resistant bacteria

Arakawa

2020

Microbiology and Immunology

Self Cite

View full text Add to dashboard Cite

In the 1980s, I found that the chromosomal β-lactamase of Klebsiella pneumoniae LEN-1 showed a very high similarity to the R-plasmid-mediated penicillinase TEM-1 on the amino acid sequence level, and this strongly suggested the origination of TEM-1 from the chromosomal penicillinases of K. pneumoniae or related bacteria. Moreover, the chromosomal K1 β-lactamase (KOXY) of Klebsiella oxytoca was found to belong to the class A β-lactamases that include LEN-1 and TEM-1, although KOXY can hydrolyze cefoperazone (CPZ) like the chromosomal AmpCtype cephalosporinases of various Enterobacteriaceae that can hydrolyze several cephalosporins including CPZ. Furthermore, my collaborators and I found plural novel serine-type β-lactamases, such as MOX-1, SHV-24, TEM-91, CTX-M-64, CMY-9, CMY-19, GES-3, GES-4, and TLA-3, mediated by plasmids. Besides these serine-type β-lactamases, we also first identified exogenously acquired metalloβ-lactamases (MBLs), IMP-1 and SMB-1, in imipenem-resistant Serratia marcescens, and the IMP-1-producing S. marcescens TN9106 became the index case for carbapenemase-producing Enterobacteriaceae. I developed the sodium mercaptoacetic acid (SMA)-disk test for the simple identification of MBL-producing bacteria. We were also the first to identify a variety of plasmid-mediated 16S ribosomal RNA methyltransferases, RmtA, RmtB, RmtC, and NpmA, from various Gram-negative bacteria that showed very high levels of resistance to a wide range of aminoglycosides. Furthermore, we first found plasmid-mediated quinolone efflux pump (QepA) and fosfomycin-inactivating enzymes (FosA3 and FosK).We also first characterized penicillin reduced susceptible Streptococcus agalactiae, macrolide-resistant Mycoplasma pneumoniae, as well as Campylobacter jejuni, and Helicobacter pylori, together with carbapenem-resistant Haemophilus influenzae.---

show abstract

Structural Insights into the TLA-3 Extended-Spectrum β-Lactamase and Its Inhibition by Avibactam and OP0595

Cited by 12 publications

References 35 publications

Structural Insights into the Inhibition of the Extended-Spectrum β-Lactamase PER-2 by Avibactam

Structural Insights into the Inhibition of the Extended-Spectrum β-Lactamase PER-2 by Avibactam

Molecular Basis for the Potent Inhibition of the Emerging Carbapenemase VCC-1 by Avibactam

Systematic research to overcome newly emerged multidrug‐resistant bacteria

Contact Info

Product

Resources

About