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One promising approach in treating antibiotic-resistant bacteria is to "break" resistances connected with antibacterial efflux by co-administering efflux pump inhibitors (EPIs) with antibiotics. Here, ten compounds, previously optimized to restore the susceptibility to ciprofloxacin (CIP) of norA-overexpressing Staphylococcus aureus, were evaluated for their ability to inhibit norA-mediated efflux in Staphylococcus pseudintermedius and synergize with CIP, ethidium bromide (EtBr), gentamycin (GEN), and chlorhexidine digluconate (CHX). We focused efforts on S. pseudintermedius as a pathogenic bacterium of concern within veterinary and human medicine. By combining data from checkerboard assays and EtBr efflux inhibition experiments, the hits 2-arylquinoline 1, dihydropyridine 6, and 2-phenyl-4-carboxy-quinoline 8 were considered the best EPIs for S. pseudintermedius. Overall, most of the compounds, except for 2-arylquinoline compound 2, were able to fully restore the susceptibility of S. pseudintermedius to CIP and synergize with GEN as well, while the synergistic effect with CHX was less significant and often did not show a dose-dependent effect. These are valuable data for medicinal chemistry optimization of EPIs for S. pseudintermedius and lay the foundation for further studies on successful EPIs to treat staphylococcal infections. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance (AMR) has become a major problem in public health leading to an estimated 4.95 million deaths in 2019. The selective pressure caused by the massive and repeated use of antibiotics has led to bacterial strains that are partially or even entirely resistant to known antibiotics. AMR is caused by several mechanisms, among which the (over)expression of multidrug efflux pumps plays a central role. Multidrug efflux pumps are transmembrane transporters, naturally expressed by Gram-negative bacteria, able to extrude and confer resistance to several classes of antibiotics. Targeting them would be an effective way to revive various options for treatment. Many efflux pump inhibitors (EPIs) have been described in the literature; however, none of them have entered clinical trials to date. This review presents eight families of EPIs active against Escherichia coli or Pseudomonas aeruginosa. Structure–activity relationships, chemical synthesis, in vitro and in vivo activities, and pharmacological properties are reported. Their binding sites and their mechanisms of action are also analyzed comparatively. [ABSTRACT FROM AUTHOR]

An effective response that combines prevention and treatment is still the most anticipated solution to the increasing incidence of antimicrobial resistance (AMR). As the phenomenon continues to evolve, AMR is driving an escalation of hard-to-treat infections and mortality rates. Over the years, bacteria have devised a variety of survival tactics to outwit the antibiotic's effects, yet given their great adaptability, unexpected mechanisms are still to be discovered. Over-expression of efflux pumps (EPs) constitutes the leading strategy of bacterial resistance, and it is also a primary driver in the establishment of multidrug resistance (MDR). Extensive efforts are being made to develop antibiotic resistance breakers (ARBs) with the ultimate goal of re-sensitizing bacteria to medications to which they have become unresponsive. EP inhibitors (EPIs) appear to be the principal group of ARBs used to impair the efflux system machinery. Due to the high toxicity of synthetic EPIs, there is a growing interest in natural, safe, and innocuous ones, whereby plant extracts emerge to be excellent candidates. Besides EPIs, further alternatives are being explored including the development of nanoparticle carriers, biologics, and phage therapy, among others. What roles do EPs play in the occurrence of MDR? What weapons do we have to thwart EP-mediated resistance? What are the obstacles to their development? These are some of the core questions addressed in the present review. [ABSTRACT FROM AUTHOR]

The menace of multidrug resistance among bacterial infections is an issue of global public health. Treatment of these superbugs with first line antibiotics is associated with significant treatment failure leading to increased mortality and morbidity. Carbapenems and polymyxins are the saviour antibiotics in case of such infections. But the problem is compounded when these antimicrobials also fail. The addition of beta-lactamase inhibitor like sulbactam and disodium ethylenediaminetetraacetic acid broaden the in vitro antibacterial action of ceftriaxone. This novel combination has been found to be effective in most of the drug resistant bacterial strains.

One promising approach in treating antibiotic-resistant bacteria is to “break” resistances connected with antibacterial efflux by co-administering efflux pump inhibitors (EPIs) with antibiotics. Here, ten compounds, previously optimized to restore the susceptibility to ciprofloxacin (CIP) of norA-overexpressing Staphylococcus aureus, were evaluated for their ability to inhibit norA-mediated efflux in Staphylococcus pseudintermedius and synergize with CIP, ethidium bromide (EtBr), gentamycin (GEN), and chlorhexidine digluconate (CHX). We focused efforts on S. pseudintermedius as a pathogenic bacterium of concern within veterinary and human medicine. By combining data from checkerboard assays and EtBr efflux inhibition experiments, the hits 2-arylquinoline 1, dihydropyridine 6, and 2-phenyl-4-carboxy-quinoline 8 were considered the best EPIs for S. pseudintermedius. Overall, most of the compounds, except for 2-arylquinoline compound 2, were able to fully restore the susceptibility of S. pseudintermedius to CIP and synergize with GEN as well, while the synergistic effect with CHX was less significant and often did not show a dose-dependent effect. These are valuable data for medicinal chemistry optimization of EPIs for S. pseudintermedius and lay the foundation for further studies on successful EPIs to treat staphylococcal infections.

Antimicrobial resistance (AMR) has become a major problem in public health leading to an estimated 4.95 million deaths in 2019. The selective pressure caused by the massive and repeated use of antibiotics has led to bacterial strains that are partially or even entirely resistant to known antibiotics. AMR is caused by several mechanisms, among which the (over)expression of multidrug efflux pumps plays a central role. Multidrug efflux pumps are transmembrane transporters, naturally expressed by Gram-negative bacteria, able to extrude and confer resistance to several classes of antibiotics. Targeting them would be an effective way to revive various options for treatment. Many efflux pump inhibitors (EPIs) have been described in the literature; however, none of them have entered clinical trials to date. This review presents eight families of EPIs active against Escherichia coli or Pseudomonas aeruginosa. Structure–activity relationships, chemical synthesis, in vitro and in vivo activities, and pharmacological properties are reported. Their binding sites and their mechanisms of action are also analyzed comparatively.

• When tcaA was deleted, all selected strains were more susceptible to β-lactams. • Ceftobiprole susceptibility was restored when tcaA was deleted. • tcaA knockout caused abnormal MRSA division. • The expression of tcaA is necessary for the upregulation of mecA when MRSA faces OXA pressure. • tcaA , which was discovered by machine learning, is a potential resistance breaker target for β-lactams in MRSA. Using a random forest algorithm, we previously found that teicoplanin-associated gene A (tcaA) might play a role in resistance of methicillin-resistant Staphylococcus aureus (MRSA) to β-lactams, which we have investigated further here. Representative MRSA strains of prevalent clones were selected to identify the role of tcaA in the MRSA response to β-lactams. tcaA genes were deleted by homologous recombination in the selected MRSA strains, and antibiotic susceptibility tests were applied to evaluate the effect of tcaA on the minimum inhibitory concentrations (MICs) of glycopeptides and β-lactams. Scanning electron microscopy, RNA sequencing, and quantitative reverse transcription-polymerase chain reaction were performed to explore the mechanism of tcaA in MRSA resistance to β-lactams. The MIC of penicillin plus clavulanate decreased from 3 mg/L to 0.064 mg/L and that of oxacillin decreased from 16 to 0.5 mg/L when tcaA was knocked out in the LAC strain. Compared with wild-type MRSA isolates, when tcaA was deleted, all selected strains were more susceptible to β-lactams. Susceptibility to ceftobiprole was restored in the ceftobiprole-resistant strain when tcaA was deleted. tcaA knockout caused "log-like" abnormal division of MRSA, and tcaA deficiency mediated low expression of mecA, ponA , and murA2. Machine learning is a reliable tool for identifying drug resistance-related genes. tcaA may be involved in S. aureus cell division and may affect mecA, ponA, and murA2 expression. Furthermore, tcaA is a potential resistance breaker target for β-lactams, including ceftobiprole, in MRSA. [Display omitted] [ABSTRACT FROM AUTHOR]

An effective response that combines prevention and treatment is still the most anticipated solution to the increasing incidence of antimicrobial resistance (AMR). As the phenomenon continues to evolve, AMR is driving an escalation of hard-to-treat infections and mortality rates. Over the years, bacteria have devised a variety of survival tactics to outwit the antibiotic’s effects, yet given their great adaptability, unexpected mechanisms are still to be discovered. Over-expression of efflux pumps (EPs) constitutes the leading strategy of bacterial resistance, and it is also a primary driver in the establishment of multidrug resistance (MDR). Extensive efforts are being made to develop antibiotic resistance breakers (ARBs) with the ultimate goal of re-sensitizing bacteria to medications to which they have become unresponsive. EP inhibitors (EPIs) appear to be the principal group of ARBs used to impair the efflux system machinery. Due to the high toxicity of synthetic EPIs, there is a growing interest in natural, safe, and innocuous ones, whereby plant extracts emerge to be excellent candidates. Besides EPIs, further alternatives are being explored including the development of nanoparticle carriers, biologics, and phage therapy, among others. What roles do EPs play in the occurrence of MDR? What weapons do we have to thwart EP-mediated resistance? What are the obstacles to their development? These are some of the core questions addressed in the present review.

The menace of multidrug resistance among bacterial infections is an issue of global public health. Treatment of these superbugs with first line antibiotics is associated with significant treatment failure leading to increased mortality and morbidity. Carbapenems and polymyxins are the saviour antibiotics in case of such infections. But the problem is compounded when these antimicrobials also fail. The addition of beta-lactamase inhibitor like sulbactam and disodium ethylenediaminetetraacetic acid broaden the in vitro antibacterial action of ceftriaxone. This novel combination has been found to be effective in most of the drug resistant bacterial strains. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance (AMR) is a complex threat to human health and, to date, it represents a hot topic in drug discovery. The use of non-antibiotic molecules to block resistance mechanisms is a powerful alternative to the identification of new antibiotics. Bacterial efflux pumps exert the early step of AMR development, allowing the bacteria to grow in presence of sub-inhibitory drug concentration and develop more specific resistance mechanisms. Thus, efflux pump inhibitors (EPIs) offer a great opportunity to fight AMR, potentially restoring antibiotic activity. Based on our experience in designing and synthesizing novel EPIs, herein, we retrieved information around quinoline and indole derivatives reported in literature on this topic. Thus, our aim was to collect all data around these promising classes of EPIs in order to delineate a comprehensive structure–activity relationship (SAR) around each core for different microbes. With this review article, we aim to help future research in the field in the discovery of new microbial EPIs with improved activity and a better safety profile.

Infections of antibiotic-resistant pathogens pose an ever-increasing threat to mankind. The investigation of novel approaches for tackling the antimicrobial resistance crisis must be part of any global response to this problem if an untimely reversion to the pre-penicillin era of medicine is to be avoided. One such promising avenue of research involves so-called antibiotic resistance breakers (ARBs), capable of re-sensitising resistant bacteria to antibiotics. Although some ARBs have previously been employed in the clinical setting, such as the β-lactam inhibitors, we posit that the broader field of ARB research can yet yield a greater diversity of more effective therapeutic agents than have been previously achieved. This review introduces the area of ARB research, summarises the current state of ARB development with emphasis on the various major classes of ARBs currently being investigated and their modes of action, and offers a perspective on the future direction of the field. [ABSTRACT FROM AUTHOR]

Objectives: In this study, we investigated the antimicrobial activity of resveratrol in combination with colistin, a last-resort agent for the treatment of severe infections caused by multidrug resistant Gram-negative pathogens.Methods: The synergistic activity and the bactericidal activity of colistin in combination with resveratrol was investigated by checkerboard assays and time-kill assays, respectively. A total of 21 strains were investigated, including 16 strains of different species (Klebsiella pneumoniae, n = 6, Escherichia coli, n = 6; Citrobacter braakii, n = 1; Stenotrophomonas malthophilia, n = 1; Enterobacter cloaceae, n = 1; Acinetobacter baumannii, n = 1) with acquired colistin resistance, three colistin-susceptible K. pneumoniae precursors, and two strains of intrinsically colistin-resistant species (Serratia marcescens, n = 1; Proteus mirabilis, n = 1). Mechanisms of acquired colistin resistance included chromosomal mutations (i.e., mgrB, pmrAB) and plasmid genes (mcr-1, mcr-1.2).Results: Resveratrol did not show any significant intrinsic antimicrobial activity. Overall, a relevant synergistic antimicrobial activity of resveratrol in combination with colistin was observed with all tested strains, except for the three colistin-susceptible K. pneumoniae strains, and for two mcr-1-positive E. coli strains. In time-kill assays, performed with 15 selected strains, the combination of colistin 2 mg/L plus resveratrol 128 mg/L was bactericidal with 11 strains, and bacteriostatic for the remaining ones.Conclusions: Resveratrol was found to potentiate colistin activity against a wide panel of colistin-resistant strains, regardless of species and resistance mechanisms, which would deserve further investigation for potential clinical applications.

Objectives: In this study, we investigated the antimicrobial activity of resveratrol in combination with colistin, a last-resort agent for the treatment of severe infections caused by multidrug resistant Gram-negative pathogens. Methods: The synergistic activity and the bactericidal activity of colistin in combination with resveratrol was investigated by checkerboard assays and time-kill assays, respectively. A total of 21 strains were investigated, including 16 strains of different species (Klebsiella pneumoniae, n = 6, Escherichia coli, n = 6; Citrobacter braakii, n = 1; Stenotrophomonas malthophilia, n = 1; Enterobacter cloaceae, n = 1 ; Acinetobacter baumannii, n = 1) with acquired colistin resistance, three colistin-susceptible K. pneumoniae precursors, and two strains of intrinsically colistin-resistant species (Serratia marcescens, n = 1; Proteus mirabilis, n = 1). Mechanisms of acquired colistin resistance included chromosomal mutations (i.e., mgrB, pmrAB) and plasmid genes (mcr-1, mcr-1.2). Results: Resveratrol did not show any significant intrinsic antimicrobial activity. Overall, a relevant synergistic antimicrobial activity of resveratrol in combination with colistin was observed with all tested strains, except for the three colistin-susceptible K. pneumoniae strains, and for two mcr-1 -positive E. coli strains. In time-kill assays, performed with 15 selected strains, the combination of colistin 2 mg/L plus resveratrol 128 mg/L was bactericidal with 11 strains, and bacteriostatic for the remaining ones. Conclusions: Resveratrol was found to potentiate colistin activity against a wide panel of colistin-resistant strains, regardless of species and resistance mechanisms, which would deserve further investigation for potential clinical applications. [ABSTRACT FROM AUTHOR]

The alarming and rapid spread of antimicrobial resistance among bacteria represents a high risk for global health. Targeting factors involved in resistance to restore the activity of failing antibiotics is a promising strategy to overcome this urgent medical need. Efflux pump inhibitors are able to increase antibiotic concentrations in bacteria, thus they can be considered true antimicrobial resistance breakers. In this work, continuing our studies on inhibitors of the Staphylococcus aureus NorA pump, we designed, synthesized and biologically evaluated novel 2-phenylquinoline derivatives starting from our hits 1 and 2 . Two of the synthesized compounds ( 6 and 7 ) bearing a C-6 benzyloxy group showed the best NorA inhibition activity, thereby providing an excellent starting point to direct future chemical optimizations. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance (AMR) represents a global health issue threatening our social lifestyle and the world economy. Efflux pumps are widely involved in AMR by playing a primary role in the development of specific mechanisms of resistance. In addition, they seem to be involved in the process of biofilm formation and maintenance, contributing to enhance the risk of creating superbugs difficult to treat. Accordingly, the identification of non-antibiotic molecules able to block efflux pumps, namely efflux pump inhibitors (EPIs), could be a promising strategy to counteract AMR and restore the antimicrobial activity of ineffective antibiotics. Herein, we enlarge the knowledge about the structure-activity relationship of 2-phenylquinoline Staphylococcus aureus NorA EPIs by reporting a new series of very potent C-6 functionalized derivatives. Best compounds significantly inhibited ethidium bromide efflux in a NorA-overexpressing S. aureus strain (SA-1199B) and strongly synergized at very low concentrations (0.20–0.78 μg/mL) with ciprofloxacin (CPX) against CPX-resistant S. aureus strains (SA-1199B and SA-K2378), as proved by checkerboard and time-kill experiments. In addition, some of these EPIs (9b and 10a) produced a post-antibiotic effect of 1.2 h and strongly enhanced antibiofilm activity of CPX against SA-1199B strain. Interestingly, at the concentrations used to reach synergy with CPX against resistant S. aureus strains, most of the EPI compounds did not show any human cell toxicity. Finally, by exploiting the recent released crystal structure of NorA, we observed that best EPI 9b highlighted a favourable docking pose, establishing some interesting interactions with key residues. [Display omitted] • C-6 functionalized 2-phenylquinoline derivatives strongly inhibit NorA efflux pump. • Properly functionalized quinoline analogues potently synergize with ciprofloxacin. • Inhibition of NorA efflux pump strongly increases the activity of fluoroquinolones. • 9b and 10a boost the activity of ciprofloxacin against Staphylococcus aureus biofilm. • The new C-6 functionalized analogue 9b interacts with the key residue Asp307 of NorA. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance (AMR) is a complex threat to human health and, to date, it represents a hot topic in drug discovery. The use of non-antibiotic molecules to block resistance mechanisms is a powerful alternative to the identification of new antibiotics. Bacterial efflux pumps exert the early step of AMR development, allowing the bacteria to grow in presence of sub-inhibitory drug concentration and develop more specific resistance mechanisms. Thus, efflux pump inhibitors (EPIs) offer a great opportunity to fight AMR, potentially restoring antibiotic activity. Based on our experience in designing and synthesizing novel EPIs, herein, we retrieved information around quinoline and indole derivatives reported in literature on this topic. Thus, our aim was to collect all data around these promising classes of EPIs in order to delineate a comprehensive structure–activity relationship (SAR) around each core for different microbes. With this review article, we aim to help future research in the field in the discovery of new microbial EPIs with improved activity and a better safety profile. [ABSTRACT FROM AUTHOR]

The Prestwick library was screened for antibacterial activity or "antibiotic resistance breaker" (ARB) potential against four species of Gram-negative pathogens. Discounting known antibacterials, the screen identified very few ARB hits, which were strain/drug specific. These ARB hits included antimetabolites (zidovudine, floxuridine, didanosine, and gemcitabine), anthracyclines (daunorubicin, mitoxantrone, and epirubicin), and psychoactive drugs (gabapentin, fluspirilene, and oxethazaine). These findings suggest that there are few approved drugs that could be directly repositioned as adjunct antibacterials, and these will need robust testing to validate efficacy., (© Crown copyright 2019.)