Antimicrobial Drug Interactions: Systematic Evaluation of Protein and Nucleic Acid Synthesis Inhibitors

Abstract

Antimicrobial multidrug resistance and its transmission among strains are serious problems. Success rate is decreased and treatment options are narrowed due to increasing bacterial multidrug resistance. On the other hand, the need for long-term efforts to discover new antibiotics and difficulties finding new treatment protocols make this problem more complex. Combination therapy, especially with synergistic use of antimicrobials is a rational treatment option with huge benefits. Thus, screening antibiotic interactions is crucial for finding better treatment options. Clinicians currently use combinatorial antibiotic treatment as an effective treatment option. However, antibiotics can show synergistic or antagonistic interactions when used together. In our study, we aimed to investigate interactions of antibiotics with different mechanisms of action. Antibiotics, which act as protein synthesis inhibitors (P) and nucleic acid synthesis inhibitors (N) were used in our study. We tested 66 (PN), 15 (NN), and 55 (PP) drug pairs on the Escherichia coli strain. The Loewe additivity model was used and alpha scores were calculated for analysis of interactions of drug combinations. Drug interactions were categorized as synergistic or antagonistic. Accordingly, pairwise combinations of protein synthesis inhibitors (PP) showed stronger synergistic interactions than those of nucleic acid synthesis inhibitors (NN) and nucleic acid synthesis–protein synthesis inhibitors (PN). As a result, the importance of mechanisms of action of drugs is emphasized in the selection of synergistic drug combinations.

A regulatory pathway that selectively up-regulates elongasome function in the absence of class A PBPs

“…In contrast, MOE and CEF together resulted in synergistic inhibition ( Figure 2—figure supplement 2 ). This is consistent with the same target drug synergy model , as previously described for E. coli protein synthesis inhibitors ( Yilancioglu, 2019 ) and drugs used to treat human diseases ( Jia et al, 2009 ), but does not support the hypothesis of CEF-dependent futile cycling.…”

Prediction of Synergistic Antibiotic Combinations by Graph Learning

“…However, as alluded to above, there are random errors in experimental measurements, which might have some impact on the classification of antibiotic combinations. As expected, we found that ROX-ERY and ROX-CHL were identified as synergistic antibiotic combinations in the experiments by Yilancioglu ( Yilancioglu, 2019 ). This means that our model has good stability for the prediction of synergistic antibiotic combinations.…”

Selenite Cystine Agar for Enumeration of Inoculated Salmonella Serovars Recovered from Stressful Conditions during Antimicrobial Validation Studies

“…Based on the antibiotic disc assay (Table 1), 'on agar' antibiotic resistance was confirmed by growing cultures in TSB (without antibiotics) and plating the cultures on TSA alone, and on TSA containing the chosen antibiotics ( Figure 3). This was done to determine if there was any antagonism that might be at play when multiple antibiotics are added in combination [34][35][36][37]. Based on the antibiotic disc assay (Table 1), 'on agar' antibiotic resistance was confirmed by growing cultures in TSB (without antibiotics) and plating the cultures on TSA alone, and on TSA containing the chosen antibiotics ( Figure 3).…”