**1. Introduction**

A chronic metabolic condition called diabetes mellitus (DM) is characterized by hyperglycemia [1].. Defining diabetic foot (DF) as "the foot of a diabetic patient who has the potential risk of pathologic consequences including infection, ulceration, and/or destruction of deep tissues associated with neurologic abnormalities, various degrees of peripheral vascular disease, and/or metabolic complications of diabetes in the lower limb," according to the World Health Organization [2]. To prevent the onset of foot ulcers, early identification of the at-risk foot should be given top

clinical attention [3]. Wound healing can be negatively impacted by stress and a steroid hormone called cortisol is high during times of stress and chronic inflammation and slows the healing of wounds. The inability of diabetic foot ulcers (DFU) to heal has been reported to be substantially correlated with CYP11B1, the enzyme that catalyzes cortisol production [4]. Cortisol levels have been linked to elevated MMP-9 levels in patients with coronary artery disease, and MMP-9 is reported to be induced and cortisol production stimulated by prostaglandin E2. The enhanced activity of matrix metalloproteinase (MMPs) is one of the causes of the resistance [5]. In 1960, the family of zinc-dependent endopeptidases known as MMPs was initially identified in tadpoles. Humans have 24 distinct MMPs that have a variety of substrates and roles [6]. MMPs are categorized in part according to the substrates they prefer to break down, including the gelatinases (MMP-2 and MMP-9), collagenases (MMP-1, MMP-8, and MMP-13), and stromelysins (MMP-3 and MMP-10) [7]. MMP expression and activity may be significantly impacted by DFU treatments that do not directly target MMPs. Most research has concentrated on the effects on MMP-9 in particular because it has long been thought that this proteinase has a role in wound healing. These investigations definitely showed that MMP-9 plays a negative effect in DFU healing, while MMP-8 plays a positive role. Approximately 15% of all diabetic patients get DFU, and of those, 84% have their lower limb amputated and 6% are hospitalized for gangrene and infections that are primarily caused by multidrug-resistant (MDR) microorganisms [8]. These pathogens include *Morganella morganii*, *Klebsiella pneumoniae*, *Proteus mirabilis*, *Streptococcus agalactiae*, *Streptococcus pyogenes*, *Streptococcus mitis*, *Staphylococcus aureus*, and *Enterococcus faecalis*, which dominate and populate the foot ulcer [9]. These pathogens exhibit virulence traits such biofilm formation and others, making antibiotic therapy ineffective against them. When bacterial colonies known as biofilms reach a certain size, they coordinate changes in gene expression *via* coordinated cell-tocell communication (quorum sensing) and prepare to express additional virulent factors [10]. The development of biofilm on the skin surface of DFU is a further issue. And in DFU, biofilm is a crucial stage in the pathophysiology and it may delay recovery. Both MDR bacteria and microorganisms that produce biofilms create antibiotic-resistant conditions that cause the lesion to become chronic, infect, and, in the worst case, necessitate lower limb amputation. Managing bacterial infections by focusing on this quorum sensing (QS)-regulated process offers a novel strategy [11]. This book chapter discusses the identification of active MMP-9 as the molecular cause of the diabetic wounds' resistance to healing as well as the unique therapeutic strategy of inhibiting enzyme proteinase and about role of inhibiting the quorum sensing (QS) system in the treatment of diabetic foot ulcer.
