Emergence of ceftazidime/avibactam non-susceptibility in an MDR Klebsiella pneumoniae isolate

Both, Anna; Büttner, Henning; Huang, Jia-Bin; Perbandt, Markus; Campos, Cristina Belmar; Martin, Coralie; Maurer, Florian P.; Kluge, Stefan; König, Christina; Aepfelbacher, Martin; Wichmann, Dominic; Rohde, Holger

doi:10.1093/jac/dkx179

Cited by 87 publications

(65 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A recently reported exception involves resistance to the ceftazidime-avibactam combination in Klebsiella pneumoniae. In this case, resistance required production of a CTX-M-14 derivative with a P 167 S substitution and additional uncharacterized ␤-lactam resistance mechanisms (12).…”

mentioning

confidence: 99%

Combination of Amino Acid Substitutions Leading to CTX-M-15-Mediated Resistance to the Ceftazidime-Avibactam Combination

Compain

Dorchêne

Arthur

2018

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Single amino acid substitutions in the Ω loop of KPC β-lactamases are known to lead to resistance to the ceftazidime-avibactam combination. Here, we investigate this mechanism of resistance in CTX-M enzymes, which are the most widely spread extended-spectrum β-lactamases worldwide. Nine single amino acid polymorphisms were identified in the Ω loop of the 172 CTX-M sequences present in the Lahey database of β-lactamases. The corresponding modifications were introduced in CTX-M-15 by site-directed mutagenesis. None of the nine substitutions was associated with ceftazidime-avibactam resistance in TOP10. However, two substitutions led to 4-fold (PS) and 16-fold (LQ) increases in the MIC of ceftazidime. We determined whether these substitutions favor the selection of mutants resistant to ceftazidime-avibactam. The selection provided mutants for the LQ substitution but not for the PS substitution or for the parental enzyme CTX-M-15. Resistance to the drug combination (MIC of ceftazidime, 16 μg/ml in the presence of 4 μg/ml of avibactam) resulted from the acquisition of the SG substitution by CTX-M-15 LQ. Purified CTX-M-15 with the two substitutions, LQ and SG, was only partially inhibited by avibactam at concentrations as high as 50,000 μM but retained ceftazidime hydrolysis activity with partially compensatory decreases in and These results indicate that emergence of resistance to the ceftazidime-avibactam combination requires more than one mutation in most CTX-M-encoding genes. Acquisition of resistance could be restricted to rare variants harboring predisposing polymorphisms such as Q at position 169 detected in a single naturally occurring CTX-M enzyme (CTX-M-93).

show abstract

mentioning

confidence: 99%

Combination of Amino Acid Substitutions Leading to CTX-M-15-Mediated Resistance to the Ceftazidime-Avibactam Combination

Compain

Dorchêne

Arthur

2018

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…When used in vivo , ceftazidime/avibactam resistance has been seen to develop in KPC producers, caused by a series of point mutations in the bla KPC gene, for example resulting in D179Y or V239G substitutions in KPC (14,15). A similar mechanism of ceftazidime/avibactam resistance was seen in CTX-M producers, with mutations in bla CTX-M , for example leading to a P170S change, alone or in addition to T264I (16).…”

Section: Introductionmentioning

confidence: 79%

“…The derivatives remained ceftazidime susceptible in the presence of 4 μg.mL −1 avibactam ( Table 2 ) which is a potent inhibitor of CTX-M (11). Replacement of bla CTX-M-14 with a gene encoding a variant associated with reduced ceftazidime/avibactam susceptibility, CTX-M-14-P170S (16) drove the ceftazidime MIC against KP21 ompK36 (pOXA-232) and KP21 M[ ompK36 ](pOXA-232) in the presence of avibactam up to 8 μg.mL −1 , which is still susceptible, but only one doubling dilution below the breakpoint for resistance. Disruption of ompK35 in KP21 M[ ompK36 ](pOXA-232)(pCTX-M-14-P170S) did not further increase the ceftazime/avibactam MIC, confirming that ramR loss-of-function phenotypically mimics ompK35 loss-of-function in this regard ( Table 2 ).…”

Section: Resultsmentioning

confidence: 99%

Resistance to Ceftazidime/Avibactam Plus Meropenem/Vaborbactam When Both are Used Together Achieved in Four Steps From Metallo-β-Lactamase NegativeKlebsiella pneumoniae

Dulyayangkul

Douglas

Lastovka

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…These inhibitors exhibit activity against βLs of classes A, C, and, partially, against class D [72,73]. However, microorganisms also develop resistance to these inhibitors [74,75]. Boronic acid derivatives are also being actively studied as novel inhibitors of βLs [76].…”

Section: Current Approaches For Overcoming the Resistance Conferred Bmentioning

confidence: 99%

The Role of the Ω-Loop in Regulation of the Catalytic Activity of TEM-Type β-Lactamases

et al. 2019

View full text Add to dashboard Cite

Bacterial resistance to β-lactams, the most commonly used class of antibiotics, poses a global challenge. This resistance is caused by the production of bacterial enzymes that are termed β-lactamases (βLs). The evolution of serine-class A β-lactamases from penicillin-binding proteins (PBPs) is related to the formation of the Ω-loop at the entrance to the enzyme's active site. In this loop, the Glu166 residue plays a key role in the two-step catalytic cycle of hydrolysis. This residue in TEM-type β-lactamases, together with Asn170, is involved in the formation of a hydrogen bonding network with a water molecule, leading to the deacylation of the acyl-enzyme complex and the hydrolysis of the β-lactam ring of the antibiotic. The activity exhibited by the Ω-loop is attributed to the positioning of its N-terminal residues near the catalytically important residues of the active site. The structure of the Ω-loop of TEM-type β-lactamases is characterized by low mutability, a stable topology, and structural flexibility. All of the revealed features of the Ω-loop, as well as the mechanisms related to its involvement in catalysis, make it a potential target for novel allosteric inhibitors of β-lactamases.Biomolecules 2019, 9, 854 2 of 16 of inhibitors, whose structures are based on the β-lactam ring, is also limited because resistance to them has also developed. Today, a promising trend is to design novel βL inhibitors and simultaneously use them with antibiotics [7,8]. Computer methods involving the in silico search of novel inhibitors has significantly broadened the range of potential inhibitors. However, only a limited number of novel βL inhibitors have been found that are of non-β-lactam nature and are capable of binding close to the enzyme's active site [8][9][10][11]. Because of the relatively low inhibition constants of such inhibitors, this area of research needs to be further developed.Recently, special attention has been paid to studying the role of loops and peptide linkers as flexible elements in the functioning of proteins and enzymes [12,13]. The loops, as secondary structural elements of proteins, are characterized by an enhanced mobility; their role is not solely confined to being connecting units [12]. Furthermore, changes in the amino acid composition of the loops may impart new functions to protein superfamilies. The Ω-loops, a special class of loops with a conformation resembling the Greek letter "omega," are currently attracting specific attention. The loop conformation is ensured by the short-distance fixation of terminal amino acids. Ω-Loops have been observed in 60 proteins [13], some of which have been found to be involved in allosteric regulation during biospecific ligand recognition [14,15]. The structure of serine class A βLs represents a compact, conserved scaffold that consists of secondary structural elements linked by flexible loops. The Ω-loop is located at the bottom of the entrance to the enzyme active site and includes the catalytically important and highly conserved residue Glu166, the m...

show abstract

Emergence of ceftazidime/avibactam non-susceptibility in an MDR Klebsiella pneumoniae isolate

Cited by 87 publications

References 38 publications

Combination of Amino Acid Substitutions Leading to CTX-M-15-Mediated Resistance to the Ceftazidime-Avibactam Combination

Combination of Amino Acid Substitutions Leading to CTX-M-15-Mediated Resistance to the Ceftazidime-Avibactam Combination

Resistance to Ceftazidime/Avibactam Plus Meropenem/Vaborbactam When Both are Used Together Achieved in Four Steps From Metallo-β-Lactamase NegativeKlebsiella pneumoniae

The Role of the Ω-Loop in Regulation of the Catalytic Activity of TEM-Type β-Lactamases

Contact Info

Product

Resources

About