Abstract
Antibiotic resistance is spreading worldwide and it has become one of the most important issues in modern medicine. In this context, the bacterial RNA degradation and processing machinery are essential processes for bacterial viability that may be exploited for antimicrobial therapy. In Staphylococcus aureus, RnpA has been hypothesized to be one of the main players in these mechanisms. S. aureus RnpA is able to modulate mRNA degradation and complex with a ribozyme (rnpB), facilitating ptRNA maturation. Corresponding small molecule screening campaigns have recently identified a few classes of RnpA inhibitors, and their structure activity relationship (SAR) has only been partially explored. Accordingly, in the present work, using computational modeling of S. aureus RnpA we identified putative crucial interactions of known RnpA inhibitors, and we used this information to design, synthesize, and biologically assess new potential RnpA inhibitors. The present results may be beneficial for the overall knowledge about RnpA inhibitors belonging to both RNPA2000-like thiosemicarbazides and JC-like piperidine carboxamides molecular classes. We evaluated the importance of the different key moieties, such as the dichlorophenyl and the piperidine of JC2, and the semithiocarbazide, the furan, and the i-propylphenyl ring of RNPA2000. Our efforts could provide a foundation for further computational-guided investigations.
Highlights
The well-documented consequences of antimicrobial resistance have been exacerbated by the limited pharmaceutical investment in new molecules [1], together with antibiotic over-prescription and misuse [2]
Antimicrobial resistance is currently surging in every country of the world, as reported by the World Health Organization (WHO) [3]
The resistance of several pathogens, such as Klebsiella pneumoniae, Escherichia coli, Mycobacterium tuberculosis, and Plasmodium falciparum, to both front line and antibiotics of last resort, are progressively leading to higher incidences of morbidity and mortality, as well as increased healthcare costs that are related to prolonged stays in hospitals [4]
Summary
The well-documented consequences of antimicrobial resistance have been exacerbated by the limited pharmaceutical investment in new molecules [1], together with antibiotic over-prescription and misuse [2]. The docking studies suggest that the reference molecules might be able to bind RnpA in the main area that was identified previously in the hotspots maps. In the subregion where the main hydrophobic hotspot was identified, there are several aromatic and hydrophobic residues, including Tyr, Phe, Leu, and Phe, where the first two are generating a cleft This might help in anchoring aromatic systems, establishing π or CH–π interactions (such as the i-propylphenyl group that is present in RnpA2000);. The central part contains a solvent-exposed area, which might allow the binding of linear linkers by establishing hydrogen bonds interactions via the backbone of Ile, Leu, Ile or the guanidinic moiety of Arg. PPrreeddiicctteeddbbinidnidnignpgopseoss, ebsa,sebdasoenddoocnkdinogcsktuindgiesst, ufodrideisf,fefroerndt cifofmerpeonutncdosmdepsoigunneddsindesigned in ththisiswwoorrkk:: ((aa))CCoommpopuonudn1d(l1ig(hlitgghretyg)rdeoyc)kdedocinkethde ipnuttahteivpeubtinadtiivneg bsiitne dcoinntgaisniitnegcaobnitpahineninylg a biphenyl scsacfaffofoldldbbeeiinngg thee aammiiddeeaabbleletotoinitnertaecrtavctiavHia-bHo-nbdowndithwLiethu4L5eaun4d5Aarngd67A. (rbg)6C7.om(bp)oCuonmd 6po(yuenl-d 6 (yellow) wlhower)ewthheerceatrhbeocnarybloinnytel rinatcetrsacwtsitwhitAhrAgr6g767anadndththioiosseemmiiccaarrbbaazzidideemmakaekseHs -Hbo-nbdonwditwh Iilteh9Ialned and Leu45. (cLC)eoCumo4p5m.o(pucno) duCno1m1d(p1oo0rua(nnbgdleu1)e0m)(abmkluainekg)imnHga-bkHoinn-gbdoHinn-tbdeorinandctteiionrnatecwrtaiicotthnioLnweuwit4hi5th,IIlIlelee9497aa,nnadnddIIllAee44r7g7,6,a7anwnddiAthArgtrh6ge76.d7(od.u)(bdl)e Compound 11am(oirdaenmgoei)emty.aking H-bond interaction with Leu, Ile, and Arg with the double amide moiety
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
