IMP10 / IMPACT Therap - LARVOL DELTA

Efficacy of imipenem combined with dimercaptosuccinic acid in a murine sepsis model using Pseudomonas aeruginosa. (PubMed, Sci Rep) - "The bactericidal and synergistic activity of imipenem plus DMSA was studied against the PAO1 reference strain of P. aeruginosa and five isogenic PAO1 strains producing the MBLs NDM-1, IMP-1, IMP-10, IMP-13, and VIM-2...In vitro, combination with DMSA increased the activity of imipenem against all MBL-producing strains and had a synergistic effect. In a murine peritoneal sepsis model, we found that combination with DMSA improved the efficacy of imipenem for NDM-1- and IMP-producers."

Journal • Preclinical • Infectious Disease • Septic Shock

The Emerging Concern of IMP Variants Being Resistant to the Only IMP-Type Metallo-ß-Lactamase Inhibitor, Xeruborbactam (ASM Microbe 2025) - "Background: Metallo-β-lactamases (MBLs) of IMP-type hydrolyze almost all β-lactams and are not inactivated by currently commercialized ß-lactamase inhibitors, including taniborbactam (TAN) which inhibit other MBLs of the NDM- and VIM-types...Susceptibility testing of cefepime, meropenem in combination with TAN or XER at 4 mg/L or 8mg/L, was performed by broth microdilution... The production of IMP-6, IMP-10, IMP-14, IMP-26 conferred resistance to XER and, therefore, to the combination MER-XER under clinical development. On the other hand, this study highlighted IMP-59, as the only IMP variant sensitive to both TAN and XER."

Infectious Disease

The emerging concern of IMP variants being resistant to the only IMP-type metallo-β-lactamase inhibitor, xeruborbactam. (PubMed, Antimicrob Agents Chemother) - "Metallo-β-lactamases (MBLs) of IMP type are not inhibited by currently commercialized β-lactamase inhibitors, including taniborbactam (TAN), which inhibits only NDM- and VIM-type enzymes. However, the development of xeruborbactam (XER), which additionally inhibits IMP enzymes, may provide effective drug combinations such as meropenem-XER (MEM-XER) against most MBL producers...Finally, structural analyses and molecular modeling simulations indicated that the Ser262Gly mutation in IMP-6 may alter the electronic properties of the active site, whereas the Phe residue in IMP-10 may exert a steric effect counteracting XER binding. Resistance to XER in IMP-6, IMP-10, IMP-14, and IMP-26 variants, conferring resistance to MEM-XER, might be considered a serious concern since MEM-XER will be supposed to be a salvage therapy for MBL-, and especially IMP-producing Enterobacterales infections."

Journal • Infectious Disease

Inhibitory activity of meso-dimercaptosuccinic acid against IMP metallo-β-lactamase variants in Pseudomonas aeruginosa. (PubMed, FEMS Microbiol Lett) - "In recombinant strains producing either IMP-1, IMP-10 or IMP-13, both with and without a functional OprD, synergy was observed to ceftazidime (CAZ), cefepime (FEP) and meropenem. Enzymatic assays showed the significantly increased inhibitory activity of DMSA against the IMP variants, compared to the other enzymes tested. These findings highlight a possible role of DMSA or DMSA-like compounds to be developed for the treatment of infections caused by IMP-producing P. aeruginosa."

Journal • Infectious Disease

The interaction of the azetidine thiazole side chain with the active site loop (ASL) 3 drives the evolution of IMP metallo-β-lactamase against tebipenem. (PubMed, Antimicrob Agents Chemother) - "To address this knowledge gap, we explored the structure activity relationships of IMP MBLs by investigating whether IMP-6, IMP-10, IMP-25, and IMP-78 [MBLs with expanded hydrolytic activity against meropenem (MEM)] would demonstrate enhanced activity against TP. These findings suggest that modifying the R2 side chain of carbapenems can significantly impact hydrolytic stability. Furthermore, changes in conformational dynamics due to single amino acid substitutions should be used to inform drug design of novel carbapenems."

Journal • VIM

Relative Inhibitory Activities of the Broad-Spectrum ß-Lactamase Inhibitor Xeruborbactam against Metallo-ß-Lactamases (ASM Microbe 2024) - "Although the newly-developed BLI taniborbactam (TAN) possesses the ability to inhibit MBL hydrolytic activities, all IMP-type enzymes and some variants such as NDM-9 and VIM-83 have been found resistant... Recombinant E. coli strains encoding a series of subclass B1 MBLs (VIM, NDM and IMP variants, together with DIM-1, GIM-1, SIM-1, SPM-1), B2 (PFM-1) or B3 (AIM-1) were constructed and susceptibility testing was performed for meropenem (MER), cefepime (FEP), ceftazidime (CAZ) and their combinations with XER (FEP-XER, CAZ-XER, MER-XER) at a fixed concentration of 4 mg/L...Noteworthy, the IMP-10 variant differing from IMP-1 by a single amino-acid substitution was found resistant to XER... This research revealed that XER exhibited a wider range of activity against B1 MBLs, but an overall weaker inhibitory activity than TAN. Noteworthy, VIM-1-like enzymes were less sensitive to XER and to TAN compared to VIM-2-like enzymes. No inhibition was observed against GIM-1, SIM-1,..."

Relative inhibitory activities of the broad-spectrum β-lactamase inhibitor xeruborbactam in comparison with taniborbactam against metallo-β-lactamases produced in Escherichia coli and Pseudomonas aeruginosa. (PubMed, Antimicrob Agents Chemother) - "As observed with taniborbactam, the combination of xeruborbactam (XER) with β-lactams, namely, ceftazidime, cefepime and meropenem, led to significantly decreased MIC values for a wide range of B1-type MBL-producing E. coli, including most recombinant strains producing NDM, VIM, IMP, GIM-1, and DIM-1 enzymes. The determination of the constant inhibition (Ki) of XER revealed a much higher value against IMP-10 than against NDM-1, VIM-2, and IMP-1. Hence, IMP-10 that differs from IMP-1 by a single amino-acid substitution (Val67Phe) can, therefore, be considered resistant to XER."

Journal

The emerging concern of IMP-10 being resistant to the only IMP-type metallo-ß-lactamase inhibitor, xeruborbactam (ECCMID 2024) - No abstract available

Tebipenem (TP) Counteracts Meropenem (MP)-Driven Evolution of IMP-1-Like Metallo-β-Lactamases (MBLs) (ASM Microbe 2023) - "In agreement with the MIC results, kcat/Km values for the TP hydrolysis were lower than those obtained for MP by IMP-1 (0.04 vs. 0.13 µM-1s-1), IMP-6 (0.16 vs. 0.28 µM-1s-1), and IMP-10 (0.07 vs. 0.44 µM-1s-1), respectively (Table 1 and Fig. TP has equal or, in case of IMPs, superior resistance to hydrolysis by clinically important MBLs. This result is remarkable as these IMP-1-like variants evolved pressured by MP exposure (PMID: 23006757). Finally, since inhibitors of MBLs are still actively sought, the decreased hydrolytic activity against TB offers the opportunity of developing a specific therapy to counteract this resistance threat."

Molecular mechanism of antimicrobial co-resistance Colistin (mcr-1) and ESBLs genes among Escherichia coli isolates from commercial chickens in Pakistan. (PubMed, Braz J Biol) - "Genotypically, followed by phenotypically of resistant ARGs of isolated PCR-confirmed E. coli (153) shoed resistant against gentamicin (aac(3)-IV), streptomycin (aadA1), tetracycline (tetA), colistine (mcr-1), ampicillin (bla-TEM) and bla-CTX-M were 86%, 88%, 86%, 88%, 83% & 77% respectively...All of E. coli isolates were found sensitive to ceftriaxone (CTX-30) and imipenem (IMP-10)...Commercial chicken (Broilers) can act as melting pot of antibiotic resistance genes for human being. It is alarming situation for surveillance of antibiotic resistance program because of more regulated prescription of antimicrobial agents in Pakistan."

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