Pyrazolo[4,3-c][1,2]benzothiazines 5,5-Dioxide: A Promising New Class of Staphylococcus aureus NorA Efflux Pump Inhibitors

Abstract

The increasing resistance to antibacterials commonly employed in the clinic and the growth of multidrug resistant strains suggest that the development of new therapeutic approaches should be of primary concern. In this context, EPIs may restore life to old drugs. In the present work, the EPI activity of the COX-2 inhibitor celecoxib was confirmed and a new class of pyrazolo­[4,3-c]­[1,2]­benzothiazine 5,5-dioxide analogues acting as inhibitors of the Staphylococcus aureus NorA multidrug efflux pump was identified.

Investigation on the effect of known potent S. aureus NorA efflux pump inhibitors on the staphylococcal biofilm formation

“…Furthermore, the few known NorA EPIs differ in terms of shape and structure and to date their mechanism of action has not been fully claried. Anyway, given our experience in the design and synthesis of NorA EPIs, [31][32][33][34] in this work we investigated the capability of previously reported potent NorA EPIs 32-34 to inhibit biolm formation in different Staphylococcus strains. To the best of our knowledge, few examples of biolm formation inhibition by EPIs in S. aureus have been reported so far, and, in any case, they concern the use of known and toxic compounds such as CCCP and TZ.…”

“…37 In parallel, the same two strains were grown in the presence of the two best NorA EPIs in an attempt to prove that, by blocking EPs, it is possible to signicantly reduce biolm mass in the overexpressing EP strain SA-1199B. and 1c 33 ) and pyrazolobenzothiazine 2 34 ( Fig. 1) were selected from our in house library of NorA EPI compounds and tested to assess their inhibition activity on biolm formation.…”

Evaluation of Different Drugs in Down-Regulation of Efflux Pump Genes expression in Methicillin-Resistant <I>Staphylococcus aureus</I> Strains

“…Resistance of microorganisms to antibiotics which is associated with several mechanisms such as enzymatic inactivation of the drugs (Sabatini et al, 2012), alteration of the drug target (s) (Ruiz et al, 2003), reduction of intracellular drug concentrations by changes in membrane permeability (Nikaido, 2003) and over expression of efflux pumps (Nikaido, 2003;Li, 2009) has become a great problem across the world. Nowadays, of these mechanisms, recently efflux pumps have been recognized as a major factor for resistance in both Gramnegative and Gram-positive bacteria (Jadwiga et al, 2013;Saiful et al, 2008).…”

“…Till date, four families of efflux pumps namely, MFS (major facilitator super family), Small Multidrug Resistance (SMR), ABC (ATP-binding cassette) and MATE (multidrug and toxic compound extrusion) have been reported in Gram-positive bacteria (Jarmula et al, 2011;Kaatz et al, 2005). Among these efflux pumps, MFS types of efflux pumps are predominantly present in Gram-positive bacteria such as NorA, NorB, MdeA, Tet38 (Staphylococcus aureus), LmrB, Bmr, Bmr3, Blt (Bacillus subtilis), MefA (Streptococcus pyogenes), MefE (Streptococcus pneumoniae) or CmlR (Streptococcus coelicor) (Jarmula et al, 2011;Borges-Walmsley et al, 2003;Poole, 2005;Markham and Neyfakh, 2001;Sabatini et al, 2012).…”

“…Several studies have shown that increased resistance to antibiotics, biocides and dyes has been associated with NorA and NorB mediated efflux pumps (Handzlik et al, 2013;Sabatini et al, 2012;Truong-Bolduc et al, 2005;Ding et al, 2008). However, antimicrobial resistance associated with NorA and NorB efflux pumps is poorly characterized in S. aureus (Handzlik et al, 2013).…”