Design and synthesis of novel and privileged small Molecules for prevention and treatment of MRSA and polymicrobial infections

T.H. Al-Tel, F.I. Al-Marzooq, S. Vunnam
University of Sharjah,
United Arab Emirates

Keywords: methicillin-resistant Staphylococcus aureus, MRSA, novel small molecules, wound infections, multidrug resistant bacteria

Summary:

Infection is the most common cause of morbidity and mortality, responsible for 61% of deaths. Accidents, disastrous, burn and combat-related injuries as well as hospital acquired infections have higher mortality rates if patients do not receive timely treatments. Both pro- and anti-inflammatory responses are involved in the post-traumatic pathologic process, and they increase the risk of acute respiratory distress syndrome, sepsis, and multiple organ failure. Unlike other types of injury, battle field, accidents and burn wounds also induce metabolic and inflammatory alterations that predispose the patient to various complications. Wounded patients, who may be immunosuppressed following trauma, are susceptible to infection by micro-organisms introduced during injury or treatment. Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most common organisms isolated from combat and injured personnel. According to the US Army Institute of Surgical Research Burn Center, 46% of burned patients were infected with Staphylococcus aureus. We have developed new synthetic methods for the synthesis of novel small molecules that represent unprecedented scaffolds, which to the best of our knowledge has never been disclosed in the literature. These compounds were tested against 10 multidrug-resistant strains of Staphylococcus species which can cause serious infections like life-threatening pneumonia and bloodstream infections. Time-kill studies were performed using one of the compounds (SIMR-1391) at a concentration between 0.78 to 100 µg/ml, compared to two standard antibiotics (ciprofloxacin and meropenem). Atomic force microscope studies of the bacterial cell wall indicated complete damage and deformation after exposure to our compound SIMR-1391. Fifteen compounds exhibited bactericidal activity against all the tested strains with minimum inhibitory concentrations (MIC) between 1.56 to 50 µg/ml. Our compounds were 10-20 times more potent than ciprofloxacin. Time-kill experiment using the compound SIMR-1391 revealed fast bactericidal activity with complete elimination of MRSA growth within 30 minutes of exposure to the compound at concentration ≥ 50 µg/ml. In comparison, ciprofloxacin, exhibited delayed killing effect with complete growth inhibition after 24 hours of exposure to the antibiotic at concentration between 32-256 µg/ml. Examination of the MRSA bacteria exposed to the compound SIMR-1391 under the atomic force microscope revealed bacterial cell shape distortion and leakage of the intracellular contents, suggesting cell wall damage due to the lytic effect of the compound ultimately led to fast cell death. The molecules were found to be safe toward normal cells and possess anti-inflammatory as well as immune potentiating activities. Due to the high potency and fast killing rate of our molecules, we propose that with the use of our lead drugs as therapeutic options, the survival of patients will improve to high rate, hospital and ICU stay and the risk of hospital acquired infections will be sharply reduced. Additionally, the use of these molecules as an adjunct to antibiotics could extend the utility, and reduce the concentrations needed (and thus the associated toxicity), of existing antibiotics.