Bio-inspired synthesis yields a tricyclic indoline that selectively resensitizes methicillin-resistant Staphylococcus aureus (MRSA) to β-lactam antibiotics

Abstract

The continuous emergence of resistant bacteria has become a major worldwide health threat. The current development of new antibacterials has lagged far behind. To discover reagents to fight against resistant bacteria, we initiated a chemical approach by synthesizing and screening a small molecule library, reminiscent of the polycyclic indole alkaloids. Indole alkaloids are a class of structurally diverse natural products, many of which were isolated from plants that have been used as traditional medicine for millennia. Specifically, we adapted an evolutionarily conserved biosynthetic strategy and developed a concise and unified diversity synthesis pathway. Using this pathway, we synthesized 120 polycyclic indolines that contain 26 distinct skeletons and a wide variety of functional groups. A tricyclic indoline, Of1, was discovered to selectively potentiate the activity of β-lactam antibiotics in multidrug-resistant methicillin-resistant Staphylococcus aureus (MRSA), but not in methicillin-sensitive S. aureus. In addition, we found that Of1 itself does not have antiproliferative activity but can resensitize several MRSA strains to the β-lactam antibiotics that are widely used in the clinic, such as an extended-spectrum β-lactam antibiotic amoxicillin/clavulanic acid and a first-generation cephalosporin cefazolin. These data suggest that Of1 is a unique selective resistancemodifying agent for β-lactam antibiotics, and it may be further developed to fight against resistant bacteria in the clinic.

Controlling bacterial behavior with indole-containing natural products and derivatives

“…The most active compound of this library, 76 , potentiated the activity of methicillin against MRSA (ATCC BAA-44), reducing the MIC from 128 to 8 μg/mL at 20 μM. 80 Compound 76 was shown to selectively resensitize this MRSA strain to all β-lactams tested, including oxacillin, imipenem and cefazolin, with high fold of potentiation (128-fold reduction in MIC for oxacillin and 32-fold for cefazolin). It was posited that 76 targets genes encoding penicillin binding protein 2a (PBP2a) and β–lactamase enzymes, but the exact mechanism of action is as yet unknown.…”

“…Synthesis of these analogues involves a one-pot three-component reaction, in which an alkyl indole species is assembled using an alkyl imine 65 , an aryl hydrazine 66 and an activating agent 67 , 80 ( Scheme 5 ). The indole regioisomers 68 and 69 underwent a gold(I)-catalyzed tandem cyclization developed by Wang and coworkers, 81 and the resulting fused ( 70 ) or spiro-tetracyclic indoline ( 71 ) was modified via alkylation or tandem ring-opening reductive amination to generate the pairs of compounds 72 , 74 and 73 , 75 respectively.…”

Bioinspired Discovery of Chemical Reactions and Biological Probes

“…20,21 Due to the efficient, one-pot nature of this approach, the rapid synthesis of a highly diverse collection of indole alkaloid-like compounds was achieved. Further structural motifs were collected by the assembly of tricyclic alkynylindole starting materials, which yielded new tetracyclic …”

“…This compound, a tricyclic indoline (Figure 2), does not directly inhibit the growth of MRSA but combats mechanisms that the bacteria activate in order to survive β-lactam antibiotics. 21 It was also discovered that 1 does not act a β-lactamase inhibitor. 23…”

Gold Approaches to Polycyclic Indole Alkaloids

“…More recently, this strategy has been adapted to the diversity-oriented synthesis (DOS) of a highly complex and diverse collection of polycyclic indoline alkaloids (Scheme 3). 8 In brief, regioisomeric alkynyl indoles 18 and 19 were prepared in a single step using a one-pot three-component reaction. 9 Under essentially the same reaction conditions, these alkynyl indoles proceeded in the predicted gold(I)-catalyzed tandem cyclizations to afford polycyclic indolines 20 and 21 as single diastereomers, respectively.…”