Late-Stage Functionalization of Platensimycin Leading to Multiple Analogues with Improved Antibacterial Activity in Vitro and in Vivo

Abstract

Bacterial fatty acid synthases are promising antibacterial targets against multi-drug resistant pathogens. Platensimycin (PTM) is a potent FabB/FabF inhibitor, while its poor pharmacokinetics hampers the clinical development. In this study, a focused library of PTM derivatives was prepared through thiolysis of PTM oxirane (1), followed by various C−C cross-coupling reactions in high yields. Antibacterial screening of these compounds in vitro yielded multiple hits with improved anti-Staphylococcus activities over PTM. Among them, compounds A1, A3, A17, and A28 exhibited improved antibacterial activities over PTM against methicillin-resistant Staphylococcus aureus (MRSA) in a mouse peritonitis model. Compound A28 was further shown to be effective against MRSA infection in a mouse wound model, in comparison to mupirocin. Therefore, the facile preparation and screening of these PTM derivatives, together with their potent antibacterial activities in vivo, suggest a promising strategy to improve the antibacterial activity and pharmacokinetic properties of PTM.

Platensimycin-Encapsulated Liposomes or Micelles as Biosafe Nanoantibiotics Exhibited Strong Antibacterial Activities against Methicillin-Resistant Staphylococcus aureus Infection in Mice

“…MRSA-infected mice treated with 10 mg/kg of PTM survived on the same day of MRSA infection, but all died on day 2. Consistent with our previous report, 23,24 these data suggested that PTM might have limited antibacterial activity in vivo by intraperitoneal injection, in contrast to the inconvenient continuous infusion route reported by Singh and coworkers. 15 Treatment of infected mice by 10 mg/kg of Lip/ PTM, M-Lip/PTM, or PLGA−PEOz/PTM led to higher survival rates of 20% to 40%, suggesting the improved in vivo efficacy over PTM.…”

“…The mouse model of acute infectious peritonitis was established by intraperitoneal injection of MRSA (2.5 × 10 7 CFU/per mouse), as previously reported (Figure 6A). 23,24 As shown in Figure 6B, the infected mice treated with saline died on the same day of the infection, while mice treated by vancomycin survived 7 days. MRSA-infected mice treated with 10 mg/kg of PTM survived on the same day of MRSA infection, but all died on day 2.…”

An Experimental Toolbox for Structure‐Based Hit Discovery for P. aeruginosa FabF, a Promising Target for Antibiotics

“…For platensimycin, this includes the modifications of the benzoic acid head group[ 26 , 27 ] and the tetracyclic cage. [ 28 , 29 , 30 , 31 , 32 ] While some of these compounds showed promising activity against Gram‐positive bacteria, for most compounds activity against Gram‐negative bacteria was not reported. In addition, poor pharmacokinetic properties were also a concern.…”

“…Total synthesis of platencin [22,23] and platensimycin [24,25] have been carried out, and efforts have been undertaken to increase the antibiotic activity through synthesis of analogues. For platensimycin, this includes the modifications of the benzoic acid head group [26,27] and the tetracyclic cage [28–32] . While some of these compounds showed promising activity against Gram‐positive bacteria, for most compounds activity against Gram‐negative bacteria was not reported.…”

An Experimental Toolbox for Structure-Based Hit Discovery for P. Aeruginosa FabF, a Promising Target for Antibiotics

“…For platensimycin this includes the modifications of the benzoic acid head group [28,29] and the tetracyclic cage. [30][31][32][33][34] While some of these compounds showed promising activity against Gram-positive bacteria, for most compounds the potency activity against Gram-negative bacteria was not reported. In addition, poor pharmacokinetic properties were also a concern.…”