**6. Cephalosporin resistance in** *S. aureus*

Similar to penicillin or other β-lactams, cephalosporins also target to bind penicillin-binding proteins (PBPs) to inhibit peptidoglycan formation in bacteria. These are effectively used in the treatment of superficial (skin and soft tissue) infections, and nosocomial and community-acquired pneumonia. Different strains of *S. aureus* strains have evolved resistance to cephalosporins, which evolved by reducing the binding affinity of cephalosporins to transpeptidase of PBPs, and also, β-lactamases are produced by bacteria having encoded plasmid for inactivation of therapeutics effect of cephalosporins. The plasmid-mediated β-lactamase resistance is corroborated by the amount and activity of the enzyme produced in bacteria.

Recent studies revealed that the prevalence of cephalosporins resistance in *S. aureus* is comparable to the β-lactamase-resistant penicillin, which accounts for 30–35% [44, 45]. Ceftaroline is the fifth-generation antibiotics, approved by the FDA in 2010, which has a broad-spectrum activity against a plethora of bacterial pathogens. Ceftaroline is active against methicillin-resistant *S. aureus* (MRSA) and has been successfully used for the treatment of different invasive bacterial infections with low adverse effects. This potent third-generation drug was found resistance in MRSA-ST293 strain in different geographical regions. Ceftaroline had the higher affinity to PBP but nonsense or missense mutations in the *mecA* gene alter the amino acid sequence of PBP protein, which causes alteration in the ceftaroline binding to PBPs. In addition, alteration of the promoter sequence of PBP4 by mutation increases PBP4 production that leads to resistance to ceftaroline [46].

### **7. Carbapenem-resistance**

The β-lactam antibiotic carbapenems are the last resort, potent, broad-spectrum antibiotic against Gram +ve and Gram –ve bacterial pathogens. They contain a carbapenem structure linked together with a beta-lactam ring, which primarily targets to bind with PBPs of the cell wall. Due to high potency, low adverse effect appeals to prefer the use of carbapenems. Prolonged and widespread uses of the drug have developed carbapenems resistance, which is contributed by a different mechanism. The resistance that arises to carbapenems is due to β-lactamase gene transfer/production, mutational alteration in PBPs, and expression of efflux pump systems [47, 48]. The carbapenem resistance is mainly contributed by β-lactamase production.

#### **8. Future perspective**

Emerging resistance in *S. aureus* is a serious human health problem, which continuously increasing mortality and morbidity rates in both nosocomial and acquired infections. The constant evolution of resistance to topical antibiotics

### *Progression of* β*-Lactam Resistance in* Staphylococcus aureus *DOI: http://dx.doi.org/10.5772/intechopen.100622*

including the continuing appearance of new resistance mechanisms and complexity in multidrug-resistant phenotypes are appealing to find new diagnostic tools and therapeutic strategies to get rid of this problem. However, a lot of toiling has continued to devise a workable treatment against staphylococcal infections particularly for the elimination of MRSA and VRSA pathogens. Emerging MDR in *S. aureus* has evolved major challenges in research and need to expend research to the next level to understand the progression of drug resistance pathways and infections pattern of *S. aureus*. The new search of therapeutics targets and bioactive molecules and their judicious use may be proven significantly to prevent the problem of drug resistance [2, 49]. Reducing the outer membrane permeability of bacterial cells can circumvent the problem of drug resistance. Iron conjugated with the antibiotic method may help to selectively interact to the outer membrane to active transport of antibiotic inside the cell [50]. Another possible approach has been targeted to inhibit quorum sensing that is primarily related to the virulence factors release and associated with the microbial pathogenesis. Chemically, virulence factors are toxic to the host cells that disrupt immune response, along with host cell disruption and cell adhesion. SarA and agr are two main quorum sensing mechanisms of *S. aureus*, which can be targeted to block the quorum sensing for controlling *S. aureus* infections. In addition, bacteriophage therapy is one of the potential methods for controlling the drug resistance in *S. aureus* infection. Phage therapy has many advantages over chemotherapy, for example, very specific, no side effect, environmental friendly, no allergenic effects, and harmless to the eukaryotic host [51]. Phage has been used to eliminate MRSA infections but is still immature in clinical application [51]. The phage-based treatment of resistant *S. aureus* will further be helpful to select the gene responsible for its control. These strategies will pave a way to develop a vaccine in future against the *S. aureus*.
