Proteome wide Identification of Therapeutic Drug Candidates against Alcaligenes faecalis

Abstract

The Alcaligenes faecalis is a gram-negative bacterium and it belongs to the family of Alcaligenaceae. It is an etiological agent of several types of infections occurred in the different parts of the human body that ultimately linked to the high degree of resistance to various classes of antibiotics. It is mainly responsible for blood stream infections, pneumonia, urinary tract infections, skin and soft tissue infections. This bacterium is a high threat to diabetic patients, as it is reported to cause foot ulcer in patients who are already diabetic. It is also involved in the production of several types of β-lactamases e.g. PER-1. The optimal temperature measured for the growth of the opportunistic bacteria A. faecalis range from 20 to 37 ◦C. The reported cases of A. faecalis are rare but fatal thereby, it is a high threat to public health and a need to develop a potential therapeutic drug that inhibits the growth of this pathogen is increasing day by day. The focus of the current study is to identify the potential drug target protein by employing the proteome wide identification approach. The subtractive proteomics revealed Elongation Factor Thermo Unstable (EF-Tu) protein as a promising drug target. Beside its canonical function in the elongation phase, it also acts as a moonlighting protein causing host immune system disruption. An AI based approach, AlphaFold, was employed to model the 3D structure of the EF-Tu. Subsequently, for comparative analysis the molecular docking of EF-Tu against three set of libraries; Asinex, FDA, and Elfamycins was performed via GOLD. Elfamycins is the family of inhibitors which includes Kirromycin, Pulvomycin, GE2270A, and Enacyloxin-II. These reported inhibitors showed lower solubility and poor pharmacokinetic profile therefore they are commercially prohibited to use against EF-Tu. To find the novel potent drug to inhibit the function of EF-Tu, several in-silico analysis such as ADMET and Toxicity analysis, MD Simulation, Atom Contacts, SASA, RDF, and Binding energy calculations were performed. Findings from this in-silico framework suggested that Fexofenadine and Enacyloxin-II are emphasizing their inhibitory efficacy thereby they could serve as a promising drug candidates against EF-Tu. The further experimental in-vivo and in-vitro validation is still required to authenticate the therapeutic and prophylactic effects of these drugs