Tetracyclic indolines as a novel class of β-lactam-selective resistance-modifying agent for MRSA

Abstract

Antibiotic-resistant bacterial infections have seen a marked increase in recent years, while antibiotic discovery has waned. Resistance-modifying agents (RMA) offer an intriguing alternative strategy to fight against resistant bacteria. Here we report the discovery, antibiotic profiling, and structure-activity relationships of a novel class of RMAs, tetracyclic indolines. These selectively potentiate β-lactam antibiotics in methicillin-resistant Staphylococcus aureus (MRSA) without antibacterial or β-lactamase inhibitory activity on their own. The most potent analogue, 6a, showed strong potentiation of amoxicillin/clavulanic acid in a variety of hospital-acquired and community-acquired MRSA strains with low mammalian toxicity. These compounds may be further developed to extend the clinic life span of β-lactam antibiotics.

Keywords: Antibiotic resistance; Indoline alkaloids; Methicillin-resistant Staphylococcus aureus; Resistance-modifying agent; Structure-activity relationship; β-lactam.

Figure 1

Structures of a series of polycyclic indole derivatives that potentiate β-lactams in MRSA.

Scheme 1. Modifications of Kf18 (4)

Reagents and conditions: a) Me₃SiI, toluene, 70 °C, 4 h; (b) for 6a, 6b, 6g, ClCOOEt, ClCOOBn, or ClSO₂Ph^pCl, DIPEA, DMAP, DMF; for 6c, triphosgene, pyridine, CH₂Cl₂, ^tBuOH, Et₃N; for 6d–f, Ac₂O, (CF₃CO)₂O or succinic anhydride, DMAP, DIPEA, DMF, rt; for 6k, 1) N,N-di Boc-N-(trifluoromethane-sulfonyl)guani-dine, Et₃N, ClCH₂CH₂Cl, 2) CH₂Cl₂, TFA; for 6h, benzyl isocyanate, Et₃N, CH₃CN; for 6i, ethyl isocyanate, DIPEA, CH₂Cl₂; for 6j, trichloroacetyl isocyanate, DIPEA, CH₂Cl₂.

Scheme 2. Synthesis of additional analogs of 4

Reagents and conditions: (a) R²OCOCl, DMAP, DMF, 23 °C, 0.5 h; 8, 0.5 h; MsOH, then 7, 60–120 °C, 24 h; (b) 5 mol% Ph₃PAuNTf₂, 50 °C, toluene; (c) R³OTf, CH₂Cl₂, 23 °C, 7 h.