Abstract
Given the increase in resistance to antibacterial agents, there is an urgent need for the development of new agents with novel modes of action. As an interim solution, it is also prudent to reinvestigate old or abandoned antibacterial compounds to assess their efficacy in the context of widespread resistance to conventional agents. In the 1970s, much work was performed on the development of peptide mimetics, exemplified by the phosphonopeptide, alafosfalin. We investigated the activity of alafosfalin, di-alanyl fosfalin and β-chloro-L-alanyl-β-chloro-L-alanine against 297 bacterial isolates, including carbapenemase-producing Enterobacterales (CPE) (n = 128), methicillin-resistant Staphylococcus aureus (MRSA) (n = 37) and glycopeptide-resistant enterococci (GRE) (n = 43). The interaction of alafosfalin with meropenem was also examined against 20 isolates of CPE. The MIC50 and MIC90 of alafosfalin for CPE were 1 mg/L and 4 mg/L, respectively and alafosfalin acted synergistically when combined with meropenem against 16 of 20 isolates of CPE. Di-alanyl fosfalin showed potent activity against glycopeptide-resistant isolates of Enterococcus faecalis (MIC90; 0.5 mg/L) and Enterococcus faecium (MIC90; 2 mg/L). Alafosfalin was only moderately active against MRSA (MIC90; 8 mg/L), whereas β-chloro-L-alanyl-β-chloro-L-alanine was slightly more active (MIC90; 4 mg/L). This study shows that phosphonopeptides, including alafosfalin, may have a therapeutic role to play in an era of increasing antibacterial resistance.
Highlights
The increasing resistance of pathogenic bacteria to antimicrobial agents is a substantial challenge to microbiologists and the medical community in general
Bacterial uptake of alafosfalin is accomplished via LL-dipeptide permeases and subsequent hydrolysis yields fosfalin (L-1-aminoethylphosphonic acid) which binds with alanine racemase; preventing synthesis of D-alanine, an essential ingredient for peptidoglycan biosynthesis [7]
Klebsiella pneumoniae was less susceptible to all of the test compounds when compared with E. coli, many isolates showed relatively low minimum inhibitory concentrations (MICs), e.g., 87% of K. pneumoniae isolates were inhibited by 8 mg/L alafosfalin
Summary
The increasing resistance of pathogenic bacteria to antimicrobial agents is a substantial challenge to microbiologists and the medical community in general. There is a worrying lack of new antimicrobials in the pharmaceutical ‘pipeline’ and the lack of options for treatment of multi-resistant Gram-negative bacteria, such as those producing carbapenemases, has been recognised for some years as a particular concern [1,2,3]. The increasing role of agents such as colistin and fosfomycin as treatment options for carbapenemase-producing Enterobacterales lends credence to this approach [5,6]. In the late 1970s, there was much interest in the use of peptide ‘mimetics’ as antibacterial agents. These typically consisted of an antibacterial compound covalently linked to one or more amino acids to facilitate uptake via the microbial peptide transport system. Alafosfalin was shown to have a broad spectrum of antibacterial activity [8] against certain Gram-positive aerobes
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