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.

Enantioselective Tandem Cyclization of Alkyne‐Tethered Indoles Using Cooperative Silver(I)/Chiral Phosphoric Acid Catalysis

“…[12] The cyclization products were further modified, leading to the discovery of two indolines, 3 and 4 (Figure 1b), that re-sensitize methicillin-resistant Staphyloco-ccus aureus (MRSA) to β-lactam antibiotics, and 5 (Figure 1b) as a novel antibacterial agent. [13] To prepare enantiomerically pure indolines for biological studies and complex indole alkaloid syntheses, we decided to develop an asymmetric cyclization. Herein, we report highly enantioselective tandem cyclizations of alkyne-tethered indoles 1 (Figure 1b) using a cooperative silver(I) and chiral phosphoric acid catalysis approach.…”

Potency of Xanthone Derivatives as antibacterial agent against Methicillin-Resistant Staphylococcus Aureus (MRSA)

“…10 This bacteria was first reported to be resistant to penicillin only 4 years after penicillin mass-production. 8 Before 1950, S. aureus had been resistant to penicillin-alternatives antibacterial like erythromycin, streptomycin, and tetracycline. In 1959, methicillin was found as an alternative for infections caused by S. aureus.…”

“…7 The discovery of antibacterial as one kind of antimicrobial agent that can eradicate bacterial were considered a revolution of health sector during the 20th centuries. 8 The history of antibacterial agents begun in 1928, when Alexander Fleming accidentally discovered penicillin for the first time. In 1929, Fleming wrote about penicillin for the first time, however at that time penicillin was not used for medical purposes, until a team from Oxford University did so in the 1940s.…”

“…10 This had been proven in 1947, only 4 years after penicillin was mass-produced, Staphylococcus aureus (S. aureus) resistance to penicillin had been reported. 8 Bacterial can develop antibacterial resistance through several mechanisms, for instance through inhibiting pathway, modifying site of action, efflux mechanism, drug-target mutation, and membrane permeabilities modification.…”

“…Among those antibacterialresistant bacterias, MRSA is the most common pathogen found in the hospitals in Asia. 8 …”