27Drug repositioning is the only feasible option to address the COVID-19 global challenge 28 immediately. We screened a panel of 48 FDA-approved drugs against SARS-CoV-2 which were 29 pre-selected by an assay of SARS-CoV and identified 24 potential antiviral drug candidates 30 against SARS-CoV-2 infection. Some drug candidates showed very low micromolar IC50s and 31 in particular, two FDA-approved drugs -niclosamide and ciclesonidewere notable in some 32 respects. 33 on June 9, 2020 by guest http://aac.asm.org/ Downloaded from 34 COVID-19 is an emerging infectious disease caused by a novel coronavirus, SARS-CoV-2 (1). 35Although the case fatality rate due to this viral infection varies from 1 to 12% (2), the 36 transmission rate is relatively high (3) and recently, the WHO declared COVID-19 outbreak a 37 pandemic. Currently, there is no vaccines or therapeutics available and the patients with COVID-38 19 are being treated with supportive care. 39Drug repositioning could be an effective strategy to respond immediately to emerging infectious 40 diseases since the new drug development usually takes more than 10 years (4). FDA-approved 41 drugs provide safe alternatives only in the case where at least modest antiviral activity can be 42 achieved. Accordingly, several drugs are being tested in numerous clinical trials (5) including 43 remdesivir, lopinavir, and chloroquine (6). 44In this study, we screened a panel of FDA-approved drugs to identify antiviral drug candidates 45 for the treatment of COVID-19 and suggest the identified drug candidates may be considered for 46 therapeutic development. 48 Results and Discussion 49We screened approximately 3,000 FDA-and IND-approved drug library against SARS-CoV to 50 identify antiviral drug candidates (manuscript in preparation). Since the SARS-CoV and SARS-51 CoV-2 are very similar (79.5% sequence identity) (1), the drugs which show antiviral activity 52 against SARS-CoV are expected to show similar extent of antiviral activity against SARS-CoV-2. 53A total of 35 drugs were selected from the earlier SARS-CoV screening results. In addition, 13 54 drugs were included based on recommendations from infectious diseases specialists (Table 1). 55For screening experiments, Vero cells were used and each drug was added to the cells prior to 56 the virus infection. At 24 h after the infection, the infected cells were scored by 57 immunofluorescence analysis with an antibody specific for the viral N protein of SARS-CoV-2. 58The confocal microscope images of both viral N protein and cell nuclei were analyzed using our 59 in-house Image Mining (IM) software and the dose-response curve (DRC) for each drug was 60 generated (Figure 1). 61 on June 9, 2020 by guest http://aac.asm.org/ Downloaded from Chloroquine, lopinavir, and remdesivir were used as reference drugs with IC 50 values of 9.12, 62 7.28, and 11.41 µM, respectively ( Figure 1A). Among the 48 drugs that were evaluated in our 63 study, 24 drugs showed potential antiviral activities against SARS-CoV-2 with IC 50 values in 64 be...

New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis, several of which are currently in clinical trials. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis.

SummaryTuberculosis continues to be a global health threat, making bicyclic nitroimidazoles an important new class of therapeutics. A deazaflavin-dependent nitroreductase (Ddn) from Mycobacterium tuberculosis catalyzes the reduction of nitroimidazoles such as PA-824, resulting in intracellular release of lethal reactive nitrogen species. The N-terminal 30 residues of Ddn are functionally important but are flexible or access multiple conformations, preventing structural characterization of the full-length, enzymatically active enzyme. Several structures were determined of a truncated, inactive Ddn protein core with and without bound F420 deazaflavin coenzyme as well as of a catalytically competent homolog from Nocardia farcinica. Mutagenesis studies based on these structures identified residues important for binding of F420 and PA-824. The proposed orientation of the tail of PA-824 toward the N terminus of Ddn is consistent with current structure-activity relationship data.

A critical unmet clinical need to combat the global tuberculosis epidemic is the development of potent agents capable of reducing the time of multi-drug-resistant (MDR) and extensively-drug-resistant (XDR) tuberculosis therapy. In this paper, we report on the optimization of imidazo[1,2-a]pyridine amide (IPA) lead compound 1, which led to the design and synthesis of Q203 (50). We found that the amide linker with IPA core is very important for activity against Mycobacterium tuberculosis H37Rv. Linearity and lipophilicity of the amine part in the IPA series play a critical role in improving in vitro and in vivo efficacy and pharmacokinetic profile. The optimized IPAs 49 and 50 showed not only excellent oral bioavailability (80.2% and 90.7%, respectively) with high exposure of the area under curve (AUC) but also displayed significant colony-forming unit (CFU) reduction (1.52 and 3.13 log10 reduction at 10 mg/kg dosing level, respectively) in mouse lung.