Abstract
While modern cephalosporins developed for broad spectrum antibacterial activities have never been pursued for tuberculosis (TB) therapy, we identified first generation cephalosporins having clinically relevant inhibitory concentrations, both alone and in synergistic drug combinations. Common chemical patterns required for activity against Mycobacterium tuberculosis were identified using structure-activity relationships (SAR) studies. Numerous cephalosporins were synergistic with rifampicin, the cornerstone drug for TB therapy, and ethambutol, a first-line anti-TB drug. Synergy was observed even under intracellular growth conditions where beta-lactams typically have limited activities. Cephalosporins and rifampicin were 4- to 64-fold more active in combination than either drug alone; however, limited synergy was observed with rifapentine or rifabutin. Clavulanate was a key synergistic partner in triple combinations. Cephalosporins (and other beta-lactams) together with clavulanate rescued the activity of rifampicin against a rifampicin resistant strain. Synergy was not due exclusively to increased rifampicin accumulation within the mycobacterial cells. Cephalosporins were also synergistic with new anti-TB drugs such as bedaquiline and delamanid. Studies will be needed to validate their in vivo activities. However, the fact that cephalosporins are orally bioavailable with good safety profiles, together with their anti-mycobacterial activities reported here, suggest that they could be repurposed within new combinatorial TB therapies.
Highlights
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is presently the most deadly infectious disease worldwide
While the activities of some beta-lactams against Mtb have been reported in recent years[14,15,16], cephalosporins have never been pursued for TB therapy[17,18]
Primary compounds were screened for synergistic interactions against our in-house assembled compound library (Sweet library; secondary compounds) that included the majority of commercially available antibiotics targeting DNA, RNA, protein, cell envelope synthesis, or essential metabolic conversions, as well as other physiologically active compounds[13]
Summary
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is presently the most deadly infectious disease worldwide. We have previously demonstrated that combinatorial drug therapy, traditionally designed to avoid emergence of drug resistant Mtb strains, might be employed to increase the efficacies of available antibiotics, allowing them to be repurposed for TB therapy within synergistic combinations[6]. Studies by Louw et al showed that efflux pump inhibitors could potentiate the activity of rifampicin against MDR strains by increasing its intracellular concentration[12] Together, these reports suggest strongly that if rifampicin activity could be increased by co-administration of a synergistic partner, therapy of drug sensitive TB disease might be shortened and the prevalence of drug resistant clinical strains reduced. We report a comprehensive study of the activities of commercially available cephalosporins against Mtb alone and in combination with synergistic partners We compared these activities with faropenem, meropenem and amoxicillin plus clavulanate (beta-lactams currently proposed for TB therapy) as a guide for further pre-clinical development
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