Mannopeptimycins, New Cyclic Glycopeptide Antibiotics Produced by Streptomyces hygroscopicus LL-AC98: Antibacterial and Mechanistic Activities

Abstract

Mannopeptimycins alpha, beta, gamma, delta, and epsilon are new cyclic glycopeptide antibiotics produced by Streptomyces hygroscopicus LL-AC98. Mannopeptimycins gamma, delta, and epsilon, which have an isovaleryl substitution at various positions on the terminal mannose of the disaccharide moiety, demonstrated moderate to good antibacterial activities. Mannopeptimycin epsilon was the most active component against methicillin-resistant staphylococci and vancomycin-resistant enterococci (MICs, 2 to 4 micro g/ml for staphylococci and streptococci and 4 to 32 micro g/ml for enterococci), while mannopeptimycins gamma and delta were two- to fourfold less active. Mannopeptimycins alpha and beta, which lack the isovaleryl substitution and the disaccharide moiety, respectively, had poor antibacterial activities. The in vivo efficacies of the mannopeptimycins in Staphylococcus aureus mouse protection studies paralleled their in vitro activities. The median effective doses of mannopeptimycins gamma, delta, and epsilon were 3.8, 2.6, and 0.59 mg/kg of body weight, respectively. The mannopeptimycins were inactive against cell wall-deficient S. aureus and caused spheroplasting of Escherichia coli imp similar to that observed with penicillin G in an osmotically protective medium. Mannopeptimycin delta rapidly inhibited [(3)H]N-acetylglucosamine incorporation into peptidoglycan in Bacillus subtilis and had no effect on DNA, RNA, or protein biosynthesis. On the basis of the observations presented above, an effect on cell wall biosynthesis was suggested as the primary mode of action for mannopeptimycin delta. The mannopeptimycins were inactive against Candida albicans, did not initiate hemolysis of human erythrocytes, and did not promote potassium ion leakage from E. coli imp, suggesting a lack of membrane damage to prokaryotic or eukaryotic cells.

Comparative In Vitro Activities of AC98-6446, a Novel Semisynthetic Glycopeptide Derivative of the Natural Product Mannopeptimycin α, and Other Antimicrobial Agents against Gram-Positive Clinical Isolates

“…The individual components of the complex are referred to as mannopeptimycin ␣ through ε. Three of these components (␥, ␦, and ε), which are simple isovalerate esters of the ␣ component, displayed moderate to good in vitro activity against susceptible gram-positive bacterial strains as well as methicillin-resistant S. aureus (MRSA), methicillin-resistant coagulase-negative staphylococci, vancomycin-resistant enterococci, and penicillin-resistant S. pneumoniae (14,30).…”

Guadinomines, Type III Secretion System Inhibitors, Produced by Streptomyces sp. K01-0509

“…1 [6]. The common substructure of the cyclic guanidinyl moiety is very unique and only a few natural products have been reported to share the substructure, namely microbial NA22598A1 [7], enduracidin [8], mannopeptimycin [9], enduracididine of plant origin [10], and anatoxin a(s) of algal origin [11] (Fig. 8).…”

In Vivo Efficacy and Pharmacokinetics of AC98-6446, a Novel Cyclic Glycopeptide, in Experimental Infection Models

“…AC98-6446 is a semisynthetic derivative belonging to the mannopeptimycin family of glycopeptide antibiotics that selectively targets bacterial cell wall synthesis (25). It has been shown to be a potent bactericidal inhibitor of resistant grampositive bacteria, including methicillin-resistant and glycopeptide-intermediate S. aureus as well as vancomycin-resistant E. faecalis and E. faecium (Petersen et al, 42nd ICAAC).…”