Cefotiam Hydrochloride

In spite of the potential for toxicity in humans, no therapeutics are approved against Epsilon toxin (ETX) for human use. Therefore, finding effective inhibitors for this toxin has garnered a lot of attention. In this regard, we performed an in silico study to find effective inhibitors against this toxin. To this end, the structure of ETX and an experimentally approved ETX inhibitor were prepared and docked as a control interaction and used for the determination of the binding site. An approved library of small molecules was obtained from the DrugBank database and prepared for virtual screening via size filtering and the addition of conformations. The top five molecules with the highest binding energy were used to draw their 2D interaction plots against ETX. A 100 ns MD simulation was performed on the Antrafenine-ETX complex as the best result of the screening stage in comparison to the control complex. The obtained results showed that among the 3849 molecules (which were analyzed by virtual screening), Cefotiam, Antrafenine, Ferric Derisomaltose, Mupirocin, and Salmeterol had the highest binding energies (binding energies respectively calculated to be -5.6, -5.8, -4.9, -4.9, and -4.6 kcal/mol). The 2D interaction plots also showed that the screened molecules had stronger interacting bonds with the ETX protein. MD simulations showed that the Antrafenine-ETX complex has a similar RMSD plot to the control complex, while its RMSF, hydrogen bond, and GR plots show better results for the Antrafenine-ETX complex. In light of these results, Antrafenine could be the best choice for ETX inhibition regarding strength, while based on the route of administration and drug applications, Cefotiam could also be considered for ETX inhibition. It seems that despite the promising results of the performed in silico studies, further empirical pieces of evidence would strengthen these conclusions in future studies.

Mycobacterium abscessus pulmonary disease is a refractory infectious disease. Developing an effective treatment is urgent as the number of patients infected with M. abscessus species (MABS) is increasing worldwide. We previously reported that nacubactam, a diazabicyclooctane (DBO) β-lactamase inhibitor, could inhibit MABS β-lactamase. Few reports have indicated that dual β-lactams are effective with a DBO β-lactamase inhibitor against MABS. The objective of this study was to determine which dual β-lactams have high antibacterial activity against MABS in the presence and absence of nacubactam.

Antimicrobial susceptibility tests were conducted through a checkerboard assay of 27 β-lactams using the broth microdilution method for three subspecies-type strains and 20 clinical isolates of MABS. The number of intracellular and extracellular bacteria was measured using human macrophages infected with M. abscessus treated with effective combinations confirmed in susceptibility tests.

In antimicrobial susceptibility tests, 91 combinations of dual β-lactams with nacubactam exhibited synergistic effects on M. abscessus JCM13569. Among them, the combination of cefazolin, cefotiam, cefoxitin, or cefuroxime with imipenem and nacubactam exhibited highly synergistic effects, resulting in low MICs against MABS clinical isolates. Without nacubactam, the combination of imipenem and cefoxitin showed the lowest MIC. In experiments using human macrophages infected with M. abscessus, these dual β-lactam combinations reduced the number of intracellular and extracellular bacteria compared with those of single β-lactams.

The combination of cefazolin, cefotiam, cefoxitin, or cefuroxime with imipenem and nacubactam was highly effective against MABS. Without nacubactam, the combination of cefoxitin and imipenem was effective.