Gram-negative bacteria are the cause of some of the deadliest infections in hospital settings. The bacteria tend to be resistant to treatment with existing antibiotics.
For decades, scientists have been finding antibiotics that work against Gram-negative bacteria. In a new study, scientists from the University of Illinois Urbana-Champaign have developed a new method to determine how antibiotics with specific chemical properties thread their way through tiny pores in the otherwise impenetrable cell envelopes of Gram-negative bacteria.
Scientists started with determining the interaction of antibiotics with different parts of the bacterial pore as it passed through at the microscopic level. One approach to tracking molecular interactions involves using supercomputers to model the chemical characteristics of every atom in a system and run simulations that reveal how the system behaves.
Scientists dubbed this technique as molecular dynamics simulation. However, the method is computationally intensive and may not track the molecular behavior of a complex system in full.
To reduce the computational load, scientists developed a method that generated the most likely pathway for the antibiotic as it wriggled through the pore. The technique allows the molecular dynamics simulations to calculate the energetics of each potential step. They ran the simulations for the antibiotic with and without the amine group attached.
University of Illinois Urbana-Champaign biochemistry professor Emad Tajkhorshid said, “Every potential pathway through the pore has an energy associated with it, and we are looking for the pathway that is energetically most favorable.”
“This effort revealed that the positively charged amine group on the antibiotic interacted favorably with negative charges lining the bacterial pore. These attractive forces allowed the antibiotic with the amine group to line up energetically more favorable as it threaded its way through the narrowest part of the pore, called the constriction zone. The antibiotic without the amine faced a higher energy barrier to passage through the pore.”
After performing experiments, scientists confirmed that the interaction between the amine and negatively charged regions of the pore enabled the passage of the antibiotic into the bacterium.
Biophysics Ph.D. student Archit Kumar Vasan said, “Understanding the precise mechanisms that allow potential antibiotics to penetrate Gram-negative bacterial cell membranes will allow scientists to design new drugs – or modify old ones – to attack and kill microbes that are otherwise resistant to treatment with antibiotics.”
Tajkhorshid said, “The technique developed to lessen the computational resources needed to address complex problems like this one also will be useful for other explorations of molecular biology.”
Biophysics Ph.D. student Nandan Haloi said, “We can use these methods to explore other disease-related processes that involve, for example, interactions between chemical compounds and proteins, how drugs bind their receptors in the body or how specific chemical groups in an antibody bind to surface antigens on a virus.”
Biochemistry research scientist Po-Chao Wen said, “Although we developed our method to study barrel-shaped proteins, this approach should be generally applicable to many other systems.”
- Nandan Haloi et al. Rationalizing the generation of broad-spectrum antibiotics with the addition of a positive charge. DOI: 10.1039/D1SC04445A