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Principal Investigator: Jianfeng Cai
Organization: UNIVERSITY OF SOUTH FLORIDA
Fiscal Year: 2024
Award: $373,750
Funding agency: National Institute of Allergy and Infectious Diseases
Antibiotic resistance has recently been identified as one of the three greatest threats facing mankind in the 21st
century by World Health Organization. One promising approach to combat antibiotic resistance is to reinvesti-
gate known antibiotics and design their derivatives, in the hope of identifying novel antibiotic agents that com-
bat antibiotic resistance. Hydantoins, the derivatives of 2,4-imidazolidinedione, have been developed for anti-
bacterial applications for long time. The mechanism of action for hydantoin derivatives is complex and not well
understood, possibly due to their damage to bacterial DNA, as well as bacterial ribosome binding and inhibition
of critical bacterial enzymes. One hydantoin derivative, nitrofurantoin, was approved to treat urinary tract infec-
tions. As an old antibiotic, it recently attracted considerable interest due to their low probability of bacterial re-
sistance compared to other conventional antibiotics such as fluoroquinolones, possibly owing to their mixed
mechanism of action. However, hydantoin derivatives including nitrofurantoin generally exhibit only moderate
antibacterial activity, which limits their further application in combating emergent antibiotic resistance.
In the last RO1 period, we have developed a series of novel antimicrobial AApeptides. Through proper de-
sign and modification, we have recently developed a series of novel membrane-active hydantoin derivatives
derived from AApeptides that display potent and broad-spectrum antimicrobial activity (25-100 fold of nitrofu-
rantoin) in vitro and in vivo. Our preliminary studies strongly suggest these compounds as a new approach for
antibiotic development. As such, our long-term goal is to develop novel antibiotic agents with novel mecha-
nisms to combat drug-resistant bacterial infections. The objective here, is to further develop these hydantoin
derivatives with greater potency through optimization of current lead compounds. Our central hypothesis is that
these agents, with proper design and modification, could be further improved in bacterial killing through novel
mechanisms. To test our central hypothesis and, thereby, accomplish the objective of this application, we will
first design and synthesize analogs of previously developed lead molecules, and identify more potent mole-
cules that are active against both Gram-positive Methicillin-resistant Staphylococcus aureus (MRSA) (MIC ≤
0.5 µg/ml) and Gram-negative Pseudomonas aeruginosa (MIC ≤ 1 µg/mL). Next, we will study if bactericidal
mechanism of lead compounds involves membrane action, and assess their probability to elicit antibiotic re-
sistance. Furthermore, we will evaluate the in vivo activity of lead compounds in a thigh-infection mouse model,
in order to demonstrate their potential as a new generation of antibiotics with novel mechanisms.
The work proposed is innovative because these compounds are a new class of hydantoin compounds that
kill both Gram-positive and Gram-negative bacteria with novel mechanisms. They are highly amendable for
derivatization and optimization, and possess low propensity to induce antibiotic resistance. The proposed work
is significant because currently there are no effective methods to combat emerging drug resistance. Our re-
search strategy will lead to a promising therapeutic approach to treat antibiotic resistant pathogens.
Terms: <Anti-Bacterial Agents><Antibiotic Agents><Antibiotic Drugs><Antibiotic Resistance><Antibiotics><Antimicrobial Resistance><Bacteria><Bacteria resistance><Bacteria resistant><Bacterial DNA><Bacterial Infections><Bacterial resistant><Binding><Biochemical><Biocompatible Materials><Biomaterials><Biophysics><Combating Antibiotic Resistant Bacteria><Complex><Data><Derivation><Derivation procedure><Development><Drug resistance><Enzyme Gene><Enzymes><Exhibits><Fluorescence Light Microscopy><Fluorescence Microscopy><Fluoroquinolones><Foundations><Generations><Goals><Gram-Negative Bacteria><Host Defense Mechanism><Hydantoins><In Vitro><Infection><Lead><Life><Literature><MRSA><Macrobid><Macrodantin><Membrane><Methicillin Resistant S. Aureus><Methods><Mice><Mice Mammals><Miscellaneous Antibiotic><Modeling><Modification><Molecular><Molecular Interaction><Multi-Drug Resistance><Multidrug Resistance><Multiple Drug Resistance><Multiple Drug Resistant><Murine><Mus><NIGMS><National Institute of General Medical Sciences><Nitrofurantoin><Outcome><P aeruginosa><P. aeruginosa><Pb element><Peptides><Probability><Pseudomonas aeruginosa><Pseudomonas pyocyanea><Publishing><Research><Resistance><Resistance to Multi-drug><Resistance to Multidrug><Resistance to Multiple Drug><Resistance to antibiotics><Resistant to Multiple Drug><Resistant to antibiotics><Resistant to multi-drug><Resistant to multidrug><Ribosomes><Series><Testing><Therapeutic><Thigh><Thigh structure><Time><Toxic effect><Toxicities><Urinary tract infection><Urinary tract infectious disease><Work><World Health Organization><analog><anti-bacterial><anti-microbial><anti-microbial agent><anti-microbial drug><anti-microbial resistant><antibiotic drug resistance><antibiotic resistance emergence><antibiotic resistant><antibiotic resistant pathogen><antimicrobial><bacteria infection><bacteria pathogen><bacterial disease><bacterial pathogen><bacterial resistance><bactericidal><bactericide><biological material><biophysical foundation><biophysical principles><biophysical sciences><clinical relevance><clinically relevant><combat><design><designing><developmental><drug resistant><drug resistant pathogen><emerging antibiotic resistance><experiment><experimental research><experimental study><experiments><heavy metal Pb><heavy metal lead><improved><in vivo><innovate><innovation><innovative><interest><membrane structure><methicillin resistance Staphylococcus aureus><methicillin resistant Staphylococcus aureus><methicillin resistant strains of Staphylococcus aureus><mouse model><multi-drug resistant><multidrug resistant><murine model><new antibiotic class><new antibiotic type><new approaches><novel><novel antibiotic class><novel approaches><novel strategies><novel strategy><pathogenic bacteria><resistance to Bacteria><resistance to Bacterial><resistance to Drug><resistance to anti-microbial><resistant><resistant to Bacteria><resistant to Bacterial><resistant to Drug><resistant to antimicrobial><small molecule><sound><urinary infection>