Development of Biphenylthiazoles Exhibiting Improved Pharmacokinetics and Potent Activity Against Intracellular <i>Staphylococcus aureus</i>

Abstract

Exploring the structure-activity relationship (SAR) at the cationic part of arylthiazole antibiotics revealed hydrazine as an active moiety. The main objective of the study is to overcome the inherited toxicity associated with the free hydrazine. A series of hydrocarbon bridges was inserted in between the groups, to separate the two amino groups. Hence, the aminomethylpiperidine-containing analog <b>16</b> was identified as a new promising antibacterial agent with efficient antibacterial and pharmacokinetic profiles. Briefly, compound <b>16</b> outperformed vancomycin in terms of the antibacterial spectrum against vancomycin-resistant staphylococcal and enterococcal strains with minimum inhibitory concentrations (MICs) ranging from 2 to 4 μg/mL, which is a faster bactericidal mode of action, completely eradicating the high staphylococcal burden within 6-8 h, and it has a unique ability to completely clear intracellular staphylococci. In addition, the initial pharmacokinetic assessment confirmed the high metabolic stability of compound <b>16</b> (biological half-life >4 h); it had a good extravascular distribution and maintained a plasma concentration higher than the average MIC value for over 12 h. Moreover, compound <b>16</b> significantly reduced MRSA burden in an <i>in vivo</i> MRSA skin infection mouse experiment. These attributes collectively suggest that compound <b>16</b> is a good therapeutic candidate for invasive staphylococcal and enterococcal infections. From a mechanistic point of view, compound <b>16</b> inhibited undecaprenyl diphosphate phosphatase (UppP) with an IC₅₀ value of 29 μM.