Phosphonopeptides Revisited, in an Era of Increasing Antimicrobial Resistance

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.

Asymmetric synthesis of organophosphorus compounds using H–P reagents derived from chiral alcohols

“…insecticides, herbicides and fungicides), [10][11][12] and finally pharmaceutically active compounds. [13][14][15][16][17][18] Selected pharmaceutically important applications of chiral organophosphorus molecules include [19][20][21][22][23][24][25][26][27] treatment of HIV and hepatitis B (Tenofovir), 19 treatment of heart failure, 20 antibiotics (Fosfamycin, 21 Valinophos, 22 Fosfazinomycin A 23 ), renin 24 and leucine aminopeptidase 25 inhibitors, antiviral agents, 26 and antibacterial and antifungal agents 27 (Fig. 1).…”

Phosphorus Compounds of Natural Origin: Prebiotic, Stereochemistry, Application

“…Phosphonopeptides of natural origin. Phosphonopeptides containing a P-C bond, like phosphopeptides, with a P-O-C bond, are relatively common substances in nature [179]. Currently, both phosphonopeptides isolated from natural sources and a significant amount of synthetic phosphonopeptides with a wide spectrum of biological activity are known.…”

“…Dehydrophos is an antibiotic isolated from Streptomyces luridus, which is effective in vivo against Salmonella-infected chickens snd has a broad spectrum of in vitro activity. Dehydrophos consists of a glycineleucin dipeptide bound to an O-methylated aminovinylphosphonate, its dehydrophosphorylation proceeds analogously to the similar in structure alaphosphine peptide and the Trojan horse peptide dehydrophosphine is imported and cleaved by peptide permeases and peptidases, respectively, to release the alanine racemase inhibitor within the cell (Figure 58) [179,180]. In recent years, a number of P-C antibiotics, possessing antifungal activity: rhizocticins [139,180], phosphonocystoximic acid [181], plumbemycins [139,182], phosphacetamycin [183], have been isolated from Bacillus subtilis and Streptomyces plumbeus.…”

Phosphonate-amidophosphate rearrangements in phosphorylated enamides and imines

“…The first can serve as surrogates for amino acids and reveal a broad spectrum of biological activity. [1][2][3][4][5][6][7][8][9][10] Phosphonamides, on the other hand, can be considered as analogues of the transition state of the hydrolysis of the peptide bond and are potent inhibitors of peptidases. 11 In addition, C,N-transfer of the phosphonyl group allows interconversions of aminophosphonates and phosphonamides.…”