Rediscovery of Tetronomycin as a Broad-Spectrum and Potent Antibiotic against Drug-Resistant Gram-Positive Bacteria

Abstract

Tetronomycin (1), first isolated from a cultured broth of Streptomyces sp. by Juslen et al. in 1974, is a polycyclic polyether compound. However, the biological activity of 1 has not been thoroughly examined. In this study, we found that 1 exhibits more potent antibacterial activity than two well-known antibacterial drugs (vancomycin and linezolid) and is effective against several drug-resistant clinical isolates including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci. Furthermore, we reassigned the 13C NMR spectra of 1 and performed a preliminary structure–activity relationship study of 1 to synthesize a chemical probe for target identification, which implied different targets based on its ionophore activity.

A new tetronomycin analog, broad‐spectrum and potent antibiotic against drug‐resistant Gram‐positive bacteria

“…As the result of the Ca 2 + ionophore activity [12] of 1 and 2, neither compound shows potent ionophore activity compared to a known ionophore compound, EDTA (ethylenediaminetetraacetic acid). Based on our previous report [6] and this study, 2 does not show significant ionophore activity even at 100 μM and the C4-5 exo-methylene group in 1 is a crucial functional group for anti-bacterial activity suggesting that 2 also have diffrent target(s) from a ionophore mechanism in the antibacterial activity.…”

“…The novel tetronomycin analog 2 (Figure 1) was isolated from the culture broth of the Streptomyces sp. K20‐0247 strain, which was previously found to produce tetronomycin ( 1 ), [5] a potential broad‐spectrum and potent antibiotic against drug‐resistant Gram‐positive bacteria that was evaluated by our group [6] . The molecular formula of 2 was revealed as C 33 H 49 O 8 (found m/z 573.3425 [M+H] + , calculated m/z 573.3427 [M+H] + ) by HR‐ESIMS.…”

“…K20-0247 strain, which was previously found to produce tetronomycin (1), [5] a potential broad-spectrum and potent antibiotic against drug-resistant Gram-positive bacteria that was evaluated by our group. [6] The molecular formula of 1).…”

“…The tetronomycin biosynthetic gene cluster (BGC) in the K20-0247 strain is highly identical to previously reported tetronomycin BGC in Streptomyces sp. NRRL 11266 (Figure S10) [6,9] These clusters possess 6 genes (tmnAI, AII, AIII, AIV, AV, and AVI) encoding polyketide synthase consisting of 13 modules. These polyketide synthases are responsible for the synthesis of the core structure of tetronomycin, and the stereochemistry of C10, C20, C24, and C28 is biosynthetically determined by these polyketide synthases (Figure S10).…”

Binding Mode-Based Physicochemical Screening Method Using d-Ala-d-Ala Silica Gel and Chemical Modification Approach to Facilitate Discovery of New Macrolactams, Banglactams A and B, from Nonomuraea bangladeshensis K18–0086

“…We screened our microbial library using D-Ala-D-Ala silica gel and found a hit culture broth of N. bangladeshensis K18−0086 (Figure S2). According to the procedure reported by us, 16 we detected a compound (Peak A) as a major component, which bound to D-Ala-D-Ala silica gel and was eluted with a solution of MeOH containing 50 mM TFA (Scheme 1). Based on liquid chromatography−mass spectrometry (LC−MS) analysis of peak A, the molecular formula of the target compound was proposed as m/z 473.3005, and we attempted to isolate the compound to characterize the structure from the 12-day-old culture broth (6 L) of the strain guided by LC-ESI-DAD-MS.…”