There is a conflict between metal ion acquisition by the pathogen and sequestration by the host. antibiotic resistance within circulating strains of is usually well documented (1). The frequency of resistance to drugs, such as clindamycin, considered to be the mainstays of antistaphylococcal therapy has increased rapidly in recent years (2), and resistance to oritavancin, the most recently US-approved drug to combat methicillin-resistant (MRSA), has already been reported (3). A clear need exists for the development of novel preventive and therapeutic approaches to combat this pathogen. The majority of available antistaphylococcal antimicrobial brokers exert their bactericidal or bacteriostatic effects by a limited number of mechanisms (Table 1). In fact, all current first-line and second-line therapies (based on expert guidance, refs. 4C6) against (MSSA), exert their antimicrobial effect via one of three mechanisms: disruption of the cell wall and/or cell membrane (-lactams, glycopeptides, lipopeptides), ribosome-targeted interference of protein synthesis (tetracyclines, macrolides, lincosamides, oxazolidinones), or inhibition of nucleotide production by disrupting folate synthesis (trimethoprim-sulfamethoxazole [TMP-SMX]) (7). In Rabbit Polyclonal to CREBZF parallel, antibiotic use has selected for strains with efficient strategies to counteract each mode of attack. A substantial number of important discoveries in the last decade have provided new insights into fundamental mechanisms, such as nutrient acquisition, key metabolic pathways, and evasion of host defenses, that allow survival in the host. In this Review, we spotlight some of these notable discoveries and discuss their clinical relevance and potential implications for developing novel interventions against this important pathogen. Table 1 Targets of intervention against in current clinical use Open in a separate windows BMS-927711 Metabolic and nutritional pathways The antimicrobial brokers TMP and SMX inhibit necessary actions in folate synthesis (8), a key metabolic pathway. These brokers are typically used synergistically and exemplify the treatment potential of targeting metabolism. Despite the great success of TMP-SMX, which has been used since the 1960s (9), no other metabolic pathwayCdisrupting antimicrobial brokers are currently approved. However, several recent studies provide encouraging targets of intervention in this area (Physique 1). Open in a separate window Physique 1 employs a variety of strategies to make sure adequate nutrition and metabolic function in resource-limited host environments.Recent insights into these pathways have revealed potential targets of intervention, as disruption of nutrient acquisition and energy production may serve to attenuate virulence. (A) A summary of metabolic adaptations of interest. is able to utilize diverse sources of substrates to generate ATP. produces a glutamate dehydrogenase (GudB) and an acetate kinase that can catabolize free amino acids from your host (32). Additionally, produces a pyruvate kinase and glucose transporters that facilitate glycolysis (27C31) and is able to scavenge free lipoic acid (33). (B) Numerous crucial steps have been recognized for the acquisition of host metals by replication and survival in the host. There is a discord between metal ion acquisition by the pathogen and sequestration by the host. The ability to overcome host sequestration is critical for staphylococcal survival, and this balance, theoretically, could be perturbed to favor the host. Perhaps the best-studied example of this host-pathogen conversation is the acquisition of iron by via uptake of host heme proteins, such as hemoglobin. In development as a human-specific pathogen. IsdB preferentially binds human hemoglobin (13); therefore, the Isd system is a logical target for intervention against susceptible to killing by light exposure (photodynamic therapy) in a murine soft-tissue contamination model (15), representing the first-known example of photosensitization of BMS-927711 by a small molecule. The uptake of other cations, such as manganese and zinc, is also essential for virulence (16). The manganese transporter MntABC is necessary for bacterial growth and resistance to oxidative stress, in part due to the crucial role of manganese as a cofactor for superoxide dismutases A and M (SodA, SodM), with SodM being unique to (17). Diminished manganese uptake renders MntABC mutants highly sensitive to killing by human neutrophils (18) and growth deficient (19). Moreover, MntABC deficiency in invasive clinical isolates similarly renders these strains sensitive to oxidative stress (20). MntC is the manganese-binding surface component BMS-927711 of MntABC; it directly competes with host calprotectin, a critical mediator of metal sequestration (21), and vaccination against MntC is usually protective in a murine model of bacteremia (22). Given the importance of manganese uptake for virulence, MntC has recently been included in both passive and active immunization regimens currently under investigation in mice and humans, respectively (23, 24). Flexible metabolism in resource-limited conditions. The remarkable ability.
