Abstract
The emergence of KPC-producing Gram-negative bacteria in clinical practice highlights the need to search for novel antimicrobials and new anti-infection strategies. In this study, we constructed a laboratory KPC-2-positive strain, E. coli BL21(DE3) (pET28a-KPC-2) and identified the activity of KPC-2 in this strain. Using enzyme inhibition assays, checkerboard MIC assays, growth curves, time-killing assays and combined disk test, we found that the natural compound corosolic acid (CA) significantly inhibited the activity of the class A β-lactamase KPC-2, which is common among clinical isolates. CA treatment increased the antibacterial or bactericidal activity of imipenem and meropenem against E. coli BL21(DE3) (pET28a-KPC-2) in vitro (FIC index = 0.17 ± 0.03 for both carbapenems). In addition, the mouse intraperitoneal infection model confirmed that the combination therapy significantly reduced the bacterial load in the livers and spleens following subcutaneous administration. Our results showed that CA can be used to extend the life of carbapenems, providing a viable strategy for severe infections caused by KPC-2-positive bacteria.
Highlights
The emergence of multidrug-resistant Gram-negative bacteria is one of the major challenges currently facing clinical medicine and livestock breeding
The Carba NP test was used to determine whether the Klebsiella pneumoniae carbapenemase (KPC)-2positive E. coli strain BL21(DE3) had the activity of carbapenemase-positive bacteria before screening KPC-2 inhibitors
Enzyme inhibition assays were used to detect the activities of KPC-2 in bacterial culture supernatants when co-cultured or co-incubated with different concentrations of corosolic acid (CA)
Summary
The emergence of multidrug-resistant Gram-negative bacteria is one of the major challenges currently facing clinical medicine and livestock breeding. The emergence and spread of these multidrug-resistant Gram-negative bacteria is fuelled by the improper use of different antibiotics, the horizontal transmission of resistance determinants, suboptimal clinical medication regimen and the frequency of international. Potential KPC-2 Inhibitor of CA exchange and cross-border travel, among other factors (Payne, 2016). To address this important issue, novel antibacterial agents, new treatment options or combination therapies are urgently needed to address serious Gram-negative pathogen infections (Liu et al, 2019). KPC-2 b-lactamase is a class A serine b-lactamase and is the most common cause of extreme resistance to b-lactam antibiotics in carbapenem-resistant Enterobacteriaceae (CRE) (Munoz-Price et al, 2013). Among the KPC variants, KPC-2 is the most widespread in Enterobacteriaceae in the United States and has shown a trend of global spread (Sanchez et al, 2013)
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