<p>Zinc Chelator N,N,N′,N′-Tetrakis(2-Pyridylmethyl)Ethylenediamine Reduces the Resistance of <em>Mycobacterium abscessus</em> to Imipenem</p>

Abstract

Imipenem is one of the very few effective options for treating Mycobacterium abscessus (M. abscessus) infections; the development of imipenem resistance is a major health concern. Materials and Methods: The susceptibility of 194 clinical M. abscessus isolates to imipenem was determined. The ability of imipenem to synergize with N,N,N′,N′-tetrakis (2-pyridylmethyl)ethylenediamine (TPEN), a zinc chelator and a metallo-β-lactamases (MBLs) inhibitor, to inhibit M. abscessus growth was also assessed. Results: M. abscessus exhibited an elevated resistance to imipenem (MIC 50 = 16 mg/L, MIC 90 = 64 mg/L). A combination of TPEN and imipenem synergized to inhibit the growth of 100% of imipenem-resistant and 79.2% of imipenem-resistance intermediate isolates; no synergy was observed treating imipenem-sensitive isolates. A remarkable decrease in the MIC 50 (from 16 to 4 mg/L) and MIC 90 (from 64 to 8 mg/L) of imipenem was observed when it was combined with TPEN; the portion of imipenem-resistant isolates also decreased (from 48.4% to 0%). Consistent with these results demonstrating synergy, a time-kill assay showed the addition of TPEN significantly improved the bactericidal activity of imipenem toward M. abscessus. Similarly, EDTA (a potent MBLs inhibitor) promoted the anti-M. abscessus activity of imipenem in a disk assay, corroborating the effect of TPEN and supporting the role of MBLs in imipenem resistance exhibited by some isolates. Conclusion: These findings demonstrate that TPEN can reduce the resistance of M. abscessus to imipenem and suggest that the inhibition of MBLs activity is the underlying mechanism.

In Vitro and In Vivo Development of a β-Lactam-Metallo-β-Lactamase Inhibitor: Targeting Carbapenem-Resistant Enterobacterales

“…A promising method to selectively target the MBLs’ mode of action is via the use of metal ion chelators that remove the essential zinc ions from the active site of the MBL enzyme. , Several scaffolds including N , N , N ′, N ′-tetrakis­(2-pyridinylmethyl)-1,2-ethanediamine (TPEN) and analogues, thiosemicarbazone, 1,4,7,10-tetraazacyclododecane (DOTA) analogues, , 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 2-picolinic acid, phosphonates rhodanine, thioenolates, magnalol, tris-picolylamines, N -acylhydrazone, 2,6-pyridine dicarboxylates (H 2 dpa’s), and 1,2,4-triazole-3-thione, have shown good activity against the New Delhi metallo β-lactamase (NDM-1) and the Verona integron-encoded MBL (VIM-2) expressing bacteria, partially restoring meropenem activity. In many cases, these chelators have been conjugated with dipeptides that mimic the bacterial cell wall sequence.…”

Neutralizing Carbapenem Resistance by Co-Administering Meropenem with Novel β-Lactam-Metallo-β-Lactamase Inhibitors

“…Many MBLI candidates produce good in vitro efficacies but fail to reach efficacy in vivo. These include NOTA [ 37 ] with poor bioavailability and TPEN [ 38 ] with cytotoxicity [ 55 ], both previously researched by our group. The data generated in Figure 7 clearly indicates the success of combination therapy in a murine infection model.…”

In vitro activity of rifabutin against Mycobacterium abscessus, clinical isolates

“…One hundred and ninety‐four clinical isolates of M. abscessus were obtained from sputum and bronchoalveolar lavage fluid samples of patients with confirmed diagonosis of M. abscessus lung disease during the period from 2012 January to 2017 December, according to the latest guideline of NTM treatment recommendations updated by The American Thoracic Society (ATS), European Respiratory Society (ERS), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), and Infectious Diseases Society of America (IDSA) in 2020 45–48 . The sources of the 194 clinical specimens were as follows: sputum ( n = 169), bronchoalveolar lavage fluid ( n = 22) and tissue ( n = 3).…”