LN-1-255, a penicillanic acid sulfone able to inhibit the class D carbapenemase OXA-48

Vallejo, Juán A.; Martínez-Guitián, Marta; Vázquez-Ucha, Juan Carlos; González‐Bello, Concepción; Poza, Margarita; Buynak, John D.; Bethel, Christopher R.; Bou, Germán; Beceiro, Alejandro

doi:10.1093/jac/dkw105

Cited by 29 publications

(29 citation statements)

References 46 publications

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“…LN-1-255 is a penicillin sulfone derivative highly effective at inhibiting OXA-48, as demonstrated in clinical isolates and in porin-deficient transformed K. pneumoniae. It has a 33-fold higher inhibition efficiency than tazobactam and binds OXA-48 very effectively (44). A focused fragment library has been set up to examine the in vitro inhibitory activity of 49 benzoic acid derivative fragments against OXA-48 as well as to observe their binding pockets and conformations (45).…”

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confidence: 99%

Treatment of Infections by OXA-48-Producing Enterobacteriaceae

Stewart

Harris

Henderson

et al. 2018

Antimicrob Agents Chemother

114

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Carbapenemase-producing (CPE) contribute significantly to the global public health threat of antimicrobial resistance. OXA-48 and its variants are unique carbapenemases with low-level hydrolytic activity toward carbapenems but no intrinsic activity against expanded-spectrum cephalosporins. is typically located on a plasmid but may also be integrated chromosomally, and this gene has progressively disseminated throughout Europe and the Middle East. Despite the inability of OXA-48-like carbapenemases to hydrolyze expanded-spectrum cephalosporins, pooled isolates demonstrate high variable resistance to ceftazidime and cefepime, likely representing high rates of extended-spectrum beta-lactamase (ESBL) coproduction. data from pooled studies suggest that avibactam is the most potent beta-lactamase inhibitor when combined with ceftazidime, cefepime, aztreonam, meropenem, or imipenem. Resistance to novel avibactam combinations such as imipenem-avibactam or aztreonam-avibactam has not yet been reported in OXA-48 producers, although only a few clinical isolates have been tested. Although combination therapy is thought to improve the chances of clinical cure and survival in CPE infection, successful outcomes were seen in ∼70% of patients with infections caused by OXA-48-producing treated with ceftazidime-avibactam monotherapy. A carbapenem in combination with either amikacin or colistin has achieved treatment success in a few case reports. Uncertainty remains regarding the best treatment options and strategies for managing these infections. Newly available antibiotics such as ceftazidime-avibactam show promise; however, recent reports of resistance are concerning. Newer choices of antimicrobial agents will likely be required to combat this problem.

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confidence: 99%

Treatment of Infections by OXA-48-Producing Enterobacteriaceae

Stewart

Harris

Henderson

et al. 2018

Antimicrob Agents Chemother

114

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“…LN-1-255, a new ␤-lactamase inhibitor, is being developed to address growing carbapenemase resistance due to CHDLs. It has been previously shown to preserve imipenem activity against OXA-48-producing strains (17) and against the most relevant CHDLs of A. baumannii (10). Porin loss seems not to affect this inhibitor, probably due to its structural similarity with siderophores (17).…”

Section: Discussionmentioning

confidence: 97%

“…The greatest advances have taken place in the development of non-␤-lactam inhibitors, especially the diazabicyclooctanones (DBOs), such as avibactam (approved for clinical use) or relebactam (in the late stage of development), which are able to inhibit class A and class C ␤-lactamases (24). Avibactam also presents activity against the relevant carbapenemase OXA-48 but does not present any activity against CHDLs of A. baumannii (17,25).…”

Section: Discussionmentioning

confidence: 99%

“…The combination of carbapenems with LN-1-255 led to an important decrease in the MICs of these antibiotics (10). Similarly, this inhibitor also demonstrated good inhibitory activity against the CHDL OXA-48, as assessed by both kinetic and microbiological studies (10,17). Other OXA or class A noncarbapenemase ␤-lactamases are also inhibited by this compound (19).…”

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confidence: 94%

“…CHDL OXA-24/40. Within a series of developed compounds, the compound LN-1-255 presented affinity in the nM range for all of the A. baumannii CHDLs tested, including the relevant OXA-23, OXA-24/40, OXA-58, and OXA-143 CHDLs (10,(16)(17)(18). The combination of carbapenems with LN-1-255 led to an important decrease in the MICs of these antibiotics (10).…”

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confidence: 99%

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Therapeutic Efficacy of LN-1-255 in Combination with Imipenem in Severe Infection Caused by Carbapenem-Resistant Acinetobacter baumannii

Vázquez-Ucha

Martínez-Guitián

Maneiro

et al. 2019

Antimicrob Agents Chemother

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The carbapenem-hydrolyzing class D β-lactamases (CHDLs) are the main mechanism of carbapenem resistance in Acinetobacter baumannii. CHDLs are not effectively inactivated by clinically available β-lactam-type inhibitors. We have previously described the in vitro efficacy of the inhibitor LN-1-255 in combination with carbapenems. The aim of this study was to compare the efficacy of LN-1-255 with that of imipenem in murine pneumonia using A. baumannii strains carrying their most extended carbapenemases, OXA-23 and OXA-24/40. The blaOXA-23 and blaOXA-24/40 genes were cloned into the carbapenem-susceptible A. baumannii ATCC 17978 strain. Clinical isolates Ab1 and JC12/04, producing the enzymes OXA-23 and OXA-24/40, respectively, were used in the study. Pharmacokinetic (PK) parameters were determined. An experimental pneumonia model was used to evaluate the efficacy of the combined imipenem–LN-1-255 therapy. MICs of imipenem decreased between 32- and 128-fold in the presence of LN-1-255. Intramuscular treatment with imipenem–LN-1-255 (30/50 mg/kg) decreased the bacterial burden by (i) 4 and 1.7 log10 CFU/g lung in the infection with the ATCC 17978-OXA-23 and Ab1 strains, respectively, and by (ii) 2.5 and 4.5 log10 CFU/g lung in the infection produced by the ATCC 17978-OXA-24/40 and the JC12/04 strains, respectively. In all assays, combined therapy offered higher protection against pneumonia than that provided by monotherapy. No toxicity was observed in treated mice. Imipenem treatment combined with LN-1-255 treatment significantly reduced the severity of infection by carbapenem-resistant A. baumannii strains carrying CHDLs. Preclinical assays demonstrated the potential of LN-1-255 and imipenem therapy as a new antibacterial treatment.

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Medicinal Chemistry of β‐Lactam Antibiotics

Testero

Llarrull

Fisher

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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The β‐lactam class of antibacterials is a cornerstone of human health. For nearly eight decades, their unparalleled clinical efficacy and clinical safety have made the β‐lactam class preeminent in the treatment of bacterial infection. The relatively brief period in human history during which the β‐lactams have exerted this benefit is a period characterized by continuous medicinal chemistry innovation, seen visibly in the progression from the penicillins to the complex ensemble of β‐lactams (now including also cephalosporins, monobactams, and carbapenems) used in the clinic. The key force behind this innovation is the progressive evolution by bacteria of resistance mechanisms. Today, highly resistant bacteria challenge the way medicinal chemists contemplate the creative alteration of β‐lactam structures, the way the pharmaceutical industry develops β‐lactams (and other antibacterial) structures, and the way the medical community uses antibacterials. This article gives a concise summary of the history of the β‐lactams. Its emphasis is recent structural innovation with respect to the β‐lactams, and with respect to structurally related classes that act to preserve the clinical activity of the β‐lactams through inhibition of bacterial β‐lactam‐hydrolyzing, and thus β‐lactam‐deactivating, enzymes. We integrate these chemistry advances with new biological discoveries with respect to the bactericidal mechanism of the β‐lactams and with respect to bacterial resistance mechanisms. The combination of these perspectives is a foundational perspective to guide the medicinal chemistry future of the β‐lactams.

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LN-1-255, a penicillanic acid sulfone able to inhibit the class D carbapenemase OXA-48

Cited by 29 publications

References 46 publications

Treatment of Infections by OXA-48-Producing Enterobacteriaceae

Treatment of Infections by OXA-48-Producing Enterobacteriaceae

Therapeutic Efficacy of LN-1-255 in Combination with Imipenem in Severe Infection Caused by Carbapenem-Resistant Acinetobacter baumannii

Medicinal Chemistry of β‐Lactam Antibiotics

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