Durlobactam sodium
[CAS# 1467157-21-6]

Identification

• Classification: API >> Synthetic anti-infective drugs
• Name: Durlobactam sodium
• Synonyms: Sodium [(2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl] sulfate
• Molecular Formula: C₈H₁₀N₃NaO₆S
• Molecular Weight: 299.24
• CAS Registry Number: 1467157-21-6
• SMILES: CC1=C[C@@H]2CN([C@@H]1C(=O)N)C(=O)N2OS(=O)(=O)[O-].[Na+]

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302-H315-H319
• Precautionary Statements: P501-P270-P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313-P301+P312+P330

Discovory and Applicatios

Durlobactam sodium is a novel β-lactamase inhibitor developed to combat bacterial resistance in infections caused by Gram-negative pathogens. It is the sodium salt form of durlobactam, a diazabicyclooctane (DBO) derivative that functions by inhibiting serine β-lactamases, enzymes responsible for the hydrolysis and inactivation of β-lactam antibiotics. This mechanism enhances the activity of β-lactam antibiotics against resistant bacterial strains, particularly Acinetobacter baumannii, a pathogen known for its multidrug resistance and role in hospital-acquired infections.

Durlobactam sodium was discovered through structure-guided medicinal chemistry approaches aimed at improving the spectrum and potency of DBO-based inhibitors. It possesses a unique molecular framework characterized by a bridged bicyclic structure that mimics the transition state of β-lactam hydrolysis. The sodium salt form is used to improve solubility and stability in pharmaceutical formulations, making it suitable for intravenous administration.

The compound is typically co-administered with sulbactam, a β-lactamase inhibitor with intrinsic antibacterial activity, especially against A. baumannii. While sulbactam alone can be degraded by resistant bacterial strains producing class A, C, and D β-lactamases, the addition of durlobactam restores its efficacy by preventing this enzymatic breakdown. This synergistic combination allows the antibacterial activity of sulbactam to be maintained even in strains producing multiple β-lactamases.

Durlobactam sodium exhibits strong inhibitory activity against a broad range of class A (e.g., TEM, SHV), class C (AmpC), and class D (OXA-type) serine β-lactamases. However, like other DBOs, it does not inhibit metallo-β-lactamases (MBLs), which require a different inhibition strategy. Its selective and reversible binding to the active site of target enzymes leads to effective inhibition without hydrolysis of the inhibitor itself, making it a stable and durable agent in β-lactamase inhibition.

The pharmacological development of durlobactam sodium has focused on intravenous formulations due to its physicochemical properties and the nature of infections it targets, such as hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP). Clinical trials have demonstrated its safety and efficacy in combination therapy, particularly in critically ill patients infected with drug-resistant *A. baumannii-calcoaceticus* complex.

In microbiological studies, durlobactam sodium has shown the ability to restore the activity of sulbactam against resistant isolates, significantly lowering the minimum inhibitory concentrations (MICs) of sulbactam. This restoration effect enables treatment options in cases where conventional β-lactam/β-lactamase inhibitor combinations have failed due to resistance development.

Chemically, durlobactam sodium is designed to be metabolically stable and to avoid rapid degradation in human plasma. It displays low protein binding and a pharmacokinetic profile compatible with co-administration alongside sulbactam. The sodium salt form provides improved aqueous solubility, essential for achieving therapeutic concentrations in systemic circulation during infusion.

In summary, durlobactam sodium represents an important advancement in the fight against multidrug-resistant Gram-negative infections. By targeting a broad spectrum of β-lactamases and enhancing the action of established β-lactam antibiotics, it supports the reintroduction of sulbactam as an effective therapeutic option against pathogens that have become increasingly difficult to treat with traditional antibiotics.

References

2017. ETX2514 is a broad-spectrum �-lactamase inhibitor for the treatment of drug-resistant Gram-negative bacteria including Acinetobacter baumannii. Nature Microbiology, 2.
DOI: 10.1038/nmicrobiol.2017.104

2020. In Vitro Activity of Sulbactam-Durlobactam against Acinetobacter baumannii-calcoaceticus Complex Isolates Collected Globally in 2016 and 2017. Antimicrobial Agents and Chemotherapy, 64(4).
DOI: 10.1128/aac.02534-19

2023. Sulbactam/Durlobactam: First Approval. Drugs, 83(12).
DOI: 10.1007/s40265-023-01920-6