Antimicrobial resistance (AMR) is of global concern, resistance to every antibiotic is not a basic requirement for a bacteria or fungi to be considered dangerous, serious problem can arise by resistance to just one antibiotic. Medicinal plants are major sources of active ingredients in prescription drugs. This current work demonstrate a one-step combinatorial strategy were antibiotics can be optimize using random selectivity of phytochemicals present in aqueous plant extract to be effective against resistant clinical isolates of Streptococcus spp, Salmonella spp, Staphylococcus aureus, Shigella spp and Escherichia coli. Concentrated sulphuric acid and 10% sodium hydroxide were used in combinatorial synthesis of Calotropis procera extract with Amoxicillin and Ampicillin at 1 mg/mL. To validate the positive results obtain in stage one, Piliostigma reticulatum extract were combined with 100 µg/mL of azithromycin and separately with 100 µg/ml of ampicillin varying the volume of the acid. Higher inhibitions zone were observed at 16.7 mm for salmonella spp, 16.4 mm shigella spp, 16.8 mm S. aureus, 21.3 mm E.coli and 22.4 mm streptococus at situations where antibiotics inhibitions zones were 0 mm. The results of this present work proposed a cost effective methods which antibiotics can be enhance to overcome resistance in bacteria using various phytochemicals present in plant extracts, this methods can be explore and applied in different ways to identify novel compounds, isolates and purify their active principles for selectivity, efficacy, safety and their development to clinical trial candidate, it may also be applied in antiviral and anticancer research to overcome enormous scientific challenges.