Natural product inspired antibacterial tetramic acid libraries with dual enzyme inhibition

Abstract

The application of natural product inspired synthesis has identified novel antibacterial tetramic acids which exhibit wide ranging antibacterial activity, and which provide potential lead structures for antibacterial drug discovery. Their phenotypic activity appears to correlate with action at two enzymes, UPPS and RNAP, which operate in independent metabolic pathways. SAR maps and identification of their relevant binding sites by molecular modelling has been achieved, and characterisation of the most active compounds suggests that these systems offer potential for topical antibiotics but that for oral and injectable use further optimisation is required.

Structural diversity of anti-pancreatic cancer capsimycins identified in mangrove-derived Streptomyces xiamenensis 318 and post-modification via a novel cytochrome P450 monooxygenase

“…Based on their unique biosynthetic origins, PTMs have multiple biological activities that involve antiprotozoal1415, antifungal71516, antibacterial91718 and antiviral actions19. They also inhibit cholesteryl ester accumulation in J774 macrophages14.…”

Fused-Ring Oxazolopyrrolopyridopyrimidine Systems with Gram-Negative Activity

“…The selectivity of a number of the test compounds ( 6a–c , 9b , 9e , 9i , 9j ) for Gram-negative ( E. coli ) activity over Gram-positive ( S. aureus ) activity is unusual and noteworthy, which we have only seen earlier with a small subset of epoxypyroglutamate systems [27,28]; by comparison, tetramate systems generally exhibit only weak Gram-negative activity but significantly stronger Gram-positive activity. Moreover, the polarity patterns are also different; in the work reported here, the most active Gram-negative systems have clogP and %PSA values in the range 1.64–1.85 and 17.6%–26.6%, respectively (Table 2), as compared to typical values of 4% and 12% observed for Gram-positive active tetramate systems [10,27]. This represents a material difference in polarity and is consistent with a requirement for higher polarity in order to achieve Gram-negative activity, to permit small molecule permeability across the Gram-negative bacterial cell wall.…”

“…Unfortunately, this realisation has come at a time when the antibacterial pipeline is poorly populated [5], and key pharmaceutical players are exiting the area. The tetramic acid core occurs in many natural products with antibacterial activity [6,7] and although the core tetramic motif itself tends to have no antibacterial activity [8], tetramates modified with acyl side chains can exhibit high levels of antibacterial (generally Gram-positive) activity [9,10]. Of interest, however, is whether the acyltetramate system is the key pharmacophore responsible for the observed biological activity, and whether the Gram-positive potency can be extended to Gram-negative activity.…”

Synthesis and antibacterial activity of monocyclic 3-carboxamide tetramic acids

“…A drug discovery programme inspired by these natural products, as promoted by Waldmann [9], was of interest to us. We have recently focused on the construction and evaluation of libraries derived from tetramic acid scaffolds and discovered that bicyclic 3-carboxamide 1e , bicyclic 3-acyl 1f and monocyclic 3-acyl 1g exhibit a dual targeting ability at RNAP and UPPS, while 3-acyl piperidine-2,4-dione 1h only targets UPPS [10]. Although tetramates are well-known as a core component in many natural products that continue to excite interest [11–14], we carried out a more detailed study of the synthesis, tautomeric behaviour and antibiotic activity of related monocyclic 3-carboxamide tetramic acid systems 2 and 3 (Schemes 1–3), the results of which are outlined below.…”