Phenylthiazole antibiotics: a multidisciplinary approach

Dr. Abdelrahman Mayhoub, Al-Azhar University, Cairo College of Pharmacy
RHPH 164
Date / Time: 
Thursday, October 12, 2017 - 4:00pm
Dr. Mark Cushman

Antimicrobial resistance (AMR) is a major global health concern. Recent alarming estimates suggest that deaths due to AMR may increase from the current estimate of 700,000 lives per year to ten million lives annually by 2050, at a cost of US$100 trillion.1, 2 Different bacterial species that were once susceptible to several different classes of antibiotics have now acquired an array of unique resistance mechanisms. For instance, several strains of Escherichia coli were recently found to be resistant to the 3rd and 4th generation carbapenems3 as well as the agent of last resort, colistin.4 However, infections caused by one notorious bacterial pathogen have proven especially difficult to treat. Out of more than 23,000 people that die each year in the United States due to antibiotic-resistant bacterial infections,5 methicillin-resistant Staphylococcus aureus (MRSA) was found to be responsible for nearly half of these fatalities. MRSA was first isolated in 1961,6, 7 and became endemic in US hospitals in mid-1980, leading to the worldwide pandemic of MRSA that continues to the present time.8, 9
S. aureus is a leading source of skin, wound, and hospital-acquired infections. Successful treatment of these infections has become a daunting challenge with the emergence of clinical isolates of MRSA exhibiting resistance to first-line antibiotics and agents of last resort, like linezolid10 and vancomycin.11 Furthermore, the effectiveness of agents of last resort (vancomycin) is limited by prolonged, persistent or recurrent bacteraemia during therapy,12, 13 high rates of clinical failures,14 severe nephrotoxicity15 and the increasing prevalence of non-susceptible strains.16 This highlights the urgent need to develop new therapeutic agents with novel scaffolds to address the burden of MRSA infections.
This lecture covers our recently discovered phenylthiazoles (PTs) class of antibacterial agents that exhibited promising antibacterial effect against several multidrug-resistant strains including MRSA, VRSA, VISA and VRE. Firstly discovered PTs exhibited several advantages of vancomycin including fast bactericidal effect. But, those advantages are plagued with short half-lives that did not exceed the limit of 30 min and rapid hepatic elimination rates. Incorporating the imine bond of the 1st generation PTs within a pyrimidine ring yielded 2nd generation analogues with enhanced metabolic stability (t1/2> 8h).17
So far, the promising antibacterial potency of 1st and 2nd generation PTs is offset by their limited activity against intracellular bacterial pathogens, similar to vancomycin and linzolid. Fine tuning of the size and polar-surface-area of the linking heteroaromatic ring provided 3rd generation PTs with balanced properties that allow them to cross and accumulate intracellularly in sufficient lethal concentrations, while keeping the metabolic stability and fast bactericidal attributes.
Later on, a detailed metabolite analysis was completed and indicated the presence of an additional metabolic soft spot at the butyl benzylic carbon.18 Addressing this limitation, by replacing the methelen soft spot with oxygen or acetylenyl moities, has yielded PTs with even more pronounced stability to hepatic metabolism.
From mechanistic point of view, the transposon mutagenesis study suggested three possible targets for PTs: YubA, YubB (undecaprenyl diphosphate phosphatase (UPPP)) and YubD. Both UPPP as well as undecaprenyl diphosphate synthase were inhibited by PT in lower micromolar IC50 values. YubA and YubD are annotated as transporters and may also be targets since tested PTs collapsed the proton motive force in membrane vesicles.19

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