Novel cyclohexyl-amides as potent antibacterials targeting bacterial type IIA topoisomerases

Mycobacterium tuberculosis Gyrase Inhibitors as a New Class of Antitubercular Drugs

“…As a consequence of the long-term efforts GSK has dedicated to the novel bacterial topoisomerase inhibitor (NBTI) field, new antibacterials with novel modes of action, no cross-resistance with FQs, oral drug-likeness, and good safety profiles have been identified (8,9,10,11). With this exercise as a starting point for TB drug discovery, a representative set of this collection (3,000 compounds) was screened against M. tuberculosis, resulting in the selection of compound leads 1 to 3 for further antitubercular profiling.…”

“…To take advantage of the broad expertise of GSK in antibacterial drug discovery, a large subset of compounds representative of the wide chemical diversity generated in the GSK novel bacterial topoisomerase inhibitor (NBTI) initiative (8,9,10,11) were evaluated in vitro against Mycobacterium tuberculosis. This exercise resulted in the identification of novel M. tuberculosis DNA gyrase inhibitors (MGIs), a new family of promising compounds with potential for the treatment of TB disease already reported in the literature as antimycobacterial and antibacterial agents (12,13,14,15).…”

A Robust Pneumonia Model in Immunocompetent Rodents to Evaluate Antibacterial Efficacy against <i>S. pneumoniae</i>, <i>H. influenzae</i>, <i>K. pneumoniae</i>, <em>P. aeruginosa</em> or <em>A. baumannii</em>

“…For some H. influenzae, there may be little growth; however, the infection should not begin to self-resolve within a 48 or 96 h time period (Figure 2B). This lung infection model can be used during optimization of lead chemical series to support SAR, as shown in Figure 3 for representative compounds of two different series 16,17 . It provides a consistent, reproducible method for assessing PK/PD in immunocompetent animals and was used to determine that free drug area under the concentration-time curve over the minimum inhibitory concentration (fAUC/MIC) correlated with efficacy of a novel polypeptide deformylase (PDF) inhibitor against S. pneumoniae and H. influenzae (Figure 4).…”

“…The multi-purpose utility of the model is demonstrated in Figures 3 and 4 and Tables 1 and 2. These studies are part of a large collection of published and unpublished data that has been generated with this model to support lead optimization efforts 16,17,[22][23][24] , for comparison and confirmation of proposed human dosing regimens 19,[25][26][27][28][29] and for PK/PD characterization It may be noted in some studies that the bacterial burden at baseline was lower than that typically targeted in other lung infection models. This is due in large part to the required dilution into agar and the small challenge volume, particularly in mice.…”

“…Reductions in bacterial burden are routinely observed for isolates considered susceptible to the agent being tested, while those considered resistant exhibit no change or bacterial growth above baseline 16,17,19,[24][25][26][27][28][29] . Studies in rats evaluating two quinolones and a macrolide using this model 32 have…”