New Approaches to Drug Discovery for Combating MRSA

Abstract

Methicillin-resistant Staphylococuss aureus (MRSA) is a major nosocomial pathogen that has developed resistance to many antibiotics. New anti-infective drugs to prevent and treat MRSA infection are required. Four assay systems were conducted to screen microbial cultures for new anti-infective compounds active against MRSA. Nosokomycins, new members of the phosphoglycolipid family, were discovered from a culture of Streptomyces cyslabdanicus K04-0144 in an MRSA-silkworm infection assay. The target molecule of nosokomycins was suggested to be the transglycosylase of penicillin binding protein (PBP) involved in MRSA peptidoglycan biosynthesis. Spirohexaline, with a hexacycline structure, was isolated from a fungal culture of Penicillium brasilianum FKI-3368 in an enzyme assay of undecaprenyl pyrophosphate (UPP) synthase, which is needed for the synthesis and transport of GlcNAc-MurNAc-pentapeptides from the cytoplasmic membrane site to the external membrane site for peptidoglycan synthesis. Spirohexaline inhibited MRSA growth by the blockade of UPP synthase activity. Cyslabdan, with a cysteine-carrying labdan skeleton, was also discovered from the nosokomycin-producing actinomycete as a potentiator of imipenem activity against MRSA. The molecular target of cyslabdan was identified as FemA, which is involved in the synthesis of a pentaglycine interpeptide bridge in MRSA peptidoglycan. Citridone A with a unique 6-6/5/5-ring system containing a rare phenyl-R-furopyridone skeleton, originally isolated as a potentiator of antifungal miconazole activity, was found to inhibit MRSA yellow pigment production. These new microbial products will serve as lead compounds for developing new anti-infective drugs for combating MRSA.

Establishment of the Inducible Tet-On System for the Activation of the Silent Trichosetin Gene Cluster in Fusarium fujikuroi

“…Trichosetin has also been found to be active against methicillin-resistant S. aureus strains at IC 50 values of ca. 30 µM, likely by interfering with the enzyme undecaprenyl pyrophosphate synthase required for peptidoglycan synthesis [29,30]. Concerning its possible application as a drug, rec assays and micronucleus tests were performed, evaluating its DNA-damaging and chromosome-breaking potential, respectively.…”

Trojan Horse Antibiotics–A Novel Way to Circumvent Gram-Negative Bacterial Resistance?

“…MRSA is still a major nosocomial pathogen, although recent additions to the armamentarium such as modified glycopeptides and oxazolidinones have recently been approved for clinical use; it is undisputed that MRSA will find a way to resist these new agents. Tomoda 33 reported on a new member of the phosphoglycolipid family, the nosokomycins from Streptomyces cyslabdanicus using a silkworm model. The proposed target site is penicillin-binding proteins specific to MRSA.…”

Diterpenoids from Streptomyces: Structures, Biosyntheses and Bioactivities

“…[84] Thus, cyslabdans may serve as lead compounds for the development of combination therapies to combat MRSA. [85] Cyclooctatin (10) was first reported as a potent lysophospholipase inhibitor without antimicrobial or cytotoxic activities. [11a] It was later reported to have antimalarial activity with an IC 50 value of 7.14 μg mL À 1 and anti-Bacillus cereus activity with an MIC value of 25.0 μg mL À 1 .…”